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Archive for the ‘Immune System’ Category

COVID-19 vaccines may not offer complete protection for people with compromised immune systems – ABC News

Sunday, May 2nd, 2021

If you have a weakened immune system, the COVID-19 vaccines may have a reduced effectiveness for you. Experts say it's still very important for you and those around you to get vaccinated, but it may be necessary for those with compromised immune systems to take extra precautions after vaccination.

"We are aware that this population may not have the same beneficial response to vaccines that we see in others who are not immunosuppressed," Dr. Linda Finn, the director of hematology and bone marrow transplant at Ochsner Health, told ABC News. "We do still recommend the vaccines, any benefit they can borrow from it, but still follow other precautions very closely."

Although clinical trials found vaccines were highly effective in preventing symptomatic or severe COVID-19 infections, these trials largely excluded people who were immunocompromised.

That means these estimates may not apply to people with weakened immune systems, such as people with cancer or HIV.

It can also include people who are taking medications that weaken the immune system to manage medical conditions, like those with autoimmune conditions or who have had transplants. Approximately 3% of the U.S. population is immunocompromised, according to the Centers for Disease Control and Preventions National Health Interview Survey.

Recent studies suggest that some of the conditions or treatments for the conditions interfere with the body's ability to create antibodies that help protect against COVID-19 after vaccination.

"It's been disheartening, obviously, for the patients to begin to realize, 'Hmm, this number of 95% effective that you hear about in the mRNA vaccine trials does not necessarily apply to me,'" Dr. Ghady Haidar, a transplant infectious disease physician at the University of Pittsburgh Medical Center, told ABC News.

A medical worker administer the Jansen (Johnson and Johnson) Covid-19 vaccine to the public at a FEMA run mobile Covid-19 Vaccination clinic at Biddeford High School in Bidderford, Maine on April 26, 2021.

Normally a fully vaccinated person will produce COVID-19 antibodies, and those antibodies should show up on an antibody test. But some fully vaccinated people who are immunocompromised have been surprised to learn they're not producing enough antibodies to test positive on an antibody test.

In one study, just over half of patients with blood, bone marrow, and lymph node cancer had antibodies; in another, less than 40% of patients with the blood cancer CLL (chronic lymphocytic leukemia) had an antibody response.

It is not yet known why this may be happening. The reduced antibody response may be due to these patients' underlying diseases, the medications they are taking, or both. Additional studies are needed to figure this out.

Experts think the vaccine should provide some protection for those who are immunocompromised, but they are still working to determine how much.

Researchers noted that antibody monitoring only measures one way the body responds to infections and there are other ways your immune system might be protecting you that wouldn't show up on an antibody test, including T-cell response, which is more challenging to test for than antibodies.

"It's definitely possible that there was still immunity built up even if the test didn't acknowledge the presence of antibodies," said Dr. John Brownstein, an epidemiologist at Boston Children's Hospital and an ABC News contributor.

"We need to develop protocols for those who are antibody negative [after vaccination]," said Dr. Mounzer Agha, a hematologist at UPMC Hillman Cancer Center and the lead author of the first study mentioned above. "The reason for testing right now would be to tell patients that they may still be vulnerable and should continue to exercise caution."

"No matter what the antibody results are, that should be the message: Continue living life safely, masking and social distancing," Haidar added.

Experts agreed that a patient's immunocompromised status is not a reason to not get a COVID-19 vaccine and that it is not only safe to do so, but very important, as they could be more at risk of becoming severely ill from COVID.

"Unless there is an absolute contraindication, which may be some allergy guidelines to avoid reactions to prior vaccines, I haven't had a patient yet that I have not advised to get the vaccine if they can," said Finn.

People with weakened immune systems will also be protected if everyone in their surrounding community is fully vaccinated, which is a concept known as "herd immunity."

Finn is recommending people get vaccinated with "what is available in their area." There is no data that favors one type or brand of vaccination over another for people with these conditions.

Experts agree that more data is needed to understand when to give vaccines to people undergoing chemotherapy, and those taking immunosuppressive medications. For now, the CDC recommends that patients starting immunosuppressive therapies get vaccinated at least two weeks prior.

Finn said it's a bit more nuanced and depends on your personal treatment plan. While she generally agrees with following the CDC's recommendations, this isn't always possible, as some patients need tighter treatment schedules with more individualized discussions.

Patients should talk to their doctors about what to do with their immunosuppressive medications and the timing of vaccination, as it may not be safe to space out, pause, or stop their medications.

Even after vaccination, people who are immunocompromised should continue to take extra precautions to avoid getting COVID-19.

"I think this patient population should expect to be following pretty broad COVID precaution guidelines for a long time," said Finn.

Some people may not know if they have a condition or take a medication that may impact the effectiveness of the vaccine. This is another reason continuing to mitigate risk with masking in crowded or indoor locations is recommended.

Haidar notes that immunocompromised people can also "encourage others around them to live their lives safely, including getting vaccinated," a step which benefits the individual and those around them.

Amanda Benarroch, M.D., is a psychiatry resident at Mayo Clinic in Rochester, Minnesota. Olivia Davies is a fourth-year student at the Medical College of Wisconsin who will be starting her residency at Massachusetts General Hospital this summer. Karine Tawagi, M.D., is a hematology and oncology fellow at Ochsner Medical Center in New Orleans. All three are contributors to the ABC News Medical Unit.

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COVID-19 vaccines may not offer complete protection for people with compromised immune systems - ABC News

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Experts say healthy diet and light exercise may boost immune response to the COVID-19 vaccine – WDJT

Sunday, May 2nd, 2021

'); if(!WVM.IS_STREAMING){ $videoEl.append('' + '' + ''); } setTimeout(function(){ $('.mute-overlay').on('touchstart click', function(e){ if(e.handled === false) return; e.stopPropagation(); e.preventDefault(); e.handled = true; player.muted(false); //console.log("volumee " + WVM.activePlayer.volume()); $(this).hide(); $(this).css('display', 'none'); var currentTime = player.currentTime(); if(currentTime 0){ if(deviceName == 'desktop'){ WVM.VIDEO_TOP = $('#media-container-' + videoId).offset().top; }else{ WVM.VIDEO_TOP = $('#media-container-' + videoId).offset().top - $('.next-dropdown-accordion').height(); } if(deviceName == 'desktop'){ WVM.VIDEO_HEIGHT = $('#html5-video-' + videoId).outerHeight(); }else{ WVM.VIDEO_HEIGHT = $('#html5-video-' + videoId).outerHeight(); } WVM.CONTAINER_HEIGHT = $('#media-container-' + videoId).height(); //console.log("container height: " + WVM.CONTAINER_HEIGHT); $(window).on( "resize", function() { if(deviceName == 'desktop'){ WVM.VIDEO_TOP = $('#media-container-' + videoId).offset().top; }else{ WVM.VIDEO_TOP = $('#media-container-' + videoId).offset().top - $('.next-dropdown-accordion').height(); } if(deviceName == 'desktop'){ WVM.VIDEO_HEIGHT = $('#html5-video-' + videoId).outerHeight(); }else{ WVM.VIDEO_HEIGHT = $('#html5-video-' + videoId).outerHeight(); } WVM.CONTAINER_HEIGHT = $('#media-container-' + videoId).height(); console.log("container height: " + WVM.CONTAINER_HEIGHT); }); //console.log("VIDEOTOP: " + WVM.VIDEO_TOP); //console.log("VIDEOHEIGHT: " + WVM.VIDEO_HEIGHT); $(window).on( "scroll", function() { if(!WVM.IS_FLOATING){ if(deviceName == 'desktop'){ WVM.CONTAINER_HEIGHT = $('#media-container-' + videoId).height(); }else{ WVM.CONTAINER_HEIGHT = $('#media-container-' + videoId + " .hlsvideo-wrapper").height() + $('#media-container-' + videoId + " .now-playing-container").height(); } } //var top = $('#media-container-' + videoId).offset().top; var offset = WVM.VIDEO_TOP + (WVM.VIDEO_HEIGHT / 2); var offsetBack = WVM.VIDEO_TOP; var changed = false; //console.log("VIDEOTOP: " + WVM.VIDEO_TOP); //console.log("VIDEOHEIGHT: " + WVM.VIDEO_HEIGHT); //console.log("scrolltop " + $(window).scrollTop()); //only float if playing var isPlaying = WVM['player_state' + videoId]['IS_PLAYING'] || WVM['player_state' + videoId]['AD_IS_PLAYING']; if(isPlaying){ $('.vjs-loading-spinner').hide(); } var offsetFloatAd = 99999999; if(deviceName == 'desktop' && $('#float_anchor').length > 0){ offsetFloatAd = $('#float_anchor').offset().top - WVM.VIDEO_HEIGHT; //console.log("float anchor offset top " + offsetFloatAd); } if($(window).scrollTop() > offset && isPlaying && !WVM['player_state' + videoId]['CANCEL_FLOATING']){ $('#media-placeholder-' + videoId).height(WVM.CONTAINER_HEIGHT); $('#media-placeholder-' + videoId).css('display', 'block'); if(!WVM.IS_FLOATING){ changed = true; } WVM.IS_FLOATING = true; $('#media-container-' + videoId).addClass('floating-video'); var sWidth = window.innerWidth || document.documentElement.clientWidth; var sHeight = window.innerHeight || document.documentElement.clientHeight; if(sWidth > 900 && WADS.IS_STICKING){ $('#media-container-' + videoId).addClass('desktop-ad-is-sticky'); } else if(WADS.IS_STICKING){ if(!TOP_AD_VIEWED){ $('#media-container-' + videoId).addClass('mobile-ad-is-sticky'); }else{ $('#media-container-' + videoId).addClass('mobile-ad-is-sticky-noad'); } } else if(!WADS.IS_STICKING){ if(!TOP_AD_VIEWED){ $('#media-container-' + videoId).removeClass('desktop-ad-is-sticky'); }else{ $('#media-container-' + videoId).addClass('desktop-ad-is-sticky-noad'); } } //set right var sWidth = window.innerWidth || document.documentElement.clientWidth; var sHeight = window.innerHeight || document.documentElement.clientHeight; if(deviceName == 'desktop' || sWidth > 900){ var leftPos2 = $('aside').get(0).getBoundingClientRect().left; var leftPos = $('aside').offset().left ; $('#media-container-' + videoId).css('left', leftPos + "px"); var newWidth = Math.floor(sWidth / 3.5); $('#media-container-' + videoId).css('width', newWidth + "px"); } else{ $('#media-container-' + videoId).css('width', "100% !important"); $('#media-container-' + videoId + ' .now-playing-container').css('display', 'block'); $('#media-container-' + videoId + ' .next-dropdown-accordion').css('display', 'block'); } //floating-video $('#media-container-' + videoId + " " + '.page-carousel-wrapper').hide(); setTimeout(function(){ var hWrapper = $('.floating-video .hlsvideo-wrapper').height(); var npWidth = $('.floating-video .now-playing-container').height(); var ndWidth = $('.floating-video .next-dropdown-header').height() + 20; var scrollerHeight = sHeight - (hWrapper + npWidth + ndWidth); scrollerHeight = 180; //scrollerHeight = parseInt(scrollerHeight * 0.5); if(WVM.device_name == 'desktop'){ $('#media-container-' + videoId + " " + " .mobile-list-videos").height(scrollerHeight); } }, 100); }else if($(window).scrollTop() 0){ var container = document.querySelector('#page-carousel-' + fullVideoId); imagesLoaded( container, function() { var screenWidth = window.innerWidth || document.documentElement.clientWidth; if(screenWidth > 850){ WVM.IS_DESKTOP = true; $('#page-carousel-' + fullVideoId + ' .page-carousel-lg-slides').css('display', 'block'); WVM['player_settings' + fullVideoId].slider = $('#page-carousel-' + fullVideoId).bxSlider({ maxSlides: 4, minSlides: 4, slideWidth: 305, infiniteLoop: false, hideControlOnEnd: true, useCSS: true, pager: false, slideMargin: 15, moveSlides: 1, nextText: '', prevText: '' }); }else{ WVM.IS_DESKTOP = false; $('.page-carousel-wrapper').css('display', 'block'); } }); } }; WVM.setupToggleButton = function(fullVideoId, player){ if($('.nextplay-switch-' + fullVideoId).length > 0){ new DG.OnOffSwitchAuto({ cls:'.nextplay-switch-' + fullVideoId, height: 24, trackColorOn:'#F9F9F9', trackColorOff:'#222', textColorOn: '#222', textColorOff: '#222', textOn:'On', textOff:'Off', listener:function(name, checked){ var theVal = 1; if(!checked){ theVal = 0; } $.ajax({ url: '/ajax/update_autoplay_video/', data: { autoplay_on: theVal }, type: 'POST', dataType: 'json', success: function(data) { WVM['player_settings' + fullVideoId]['autoplay'] = checked; }, error : function(){ console.log("Error loading video"); } }); } }); } }; WVM.setupAccordionButton = function(fullVideoId){ var deviceName = 'desktop'; $('#next-dropdown-accordion-button-' + fullVideoId).on('click', function(){ if($(this).find('i').hasClass('fa-chevron-up')){ //hide $(this).find('i').removeClass('fa-chevron-up'); $(this).find('i').addClass('fa-chevron-down'); if(deviceName == "desktop" && !$('#media-container-' + fullVideoId).hasClass('floating-video')){ $('#media-container-' + fullVideoId + " " + '.page-carousel-wrapper').slideUp(); $('#media-container-' + fullVideoId + " " + '.mobile-list-wrapper').hide(); }else{ $('#media-container-' + fullVideoId + " " + '.mobile-list-wrapper').slideUp(); $('#media-container-' + fullVideoId + " " + '.page-carousel-wrapper').hide(); } var currVideoId = WVM['player_state' + fullVideoId]['VIDEO_ID']; var nextVideoId = WVM.getNextPlaylistIndex(currVideoId); //playerId, mediaId, fieldName var myTitle = WVM.getPlaylistData(fullVideoId, nextVideoId, 'noprefixtitle'); //alert("Getting title " + myTitle); $('#video-slider-nexttitle' + fullVideoId).css('display', 'inline'); $('#video-slider-nexttitle' + fullVideoId).html(myTitle); }else{ //expand $(this).find('i').addClass('fa-chevron-up'); $(this).find('i').removeClass('fa-chevron-down'); $('#media-container-' + fullVideoId + " " + '.mobile-list-wrapper').css('display', 'block'); if(deviceName == "desktop" && !$('#media-container-' + fullVideoId).hasClass('floating-video')){ $('#media-container-' + fullVideoId + " " + '.page-carousel-wrapper').css('display', 'block'); $('#media-container-' + fullVideoId + " " + '.page-carousel-wrapper').slideDown(); $('#media-container-' + fullVideoId + " " + '.mobile-list-wrapper').hide(); if(!WVM.player_state155200['CAROUSEL_INIT']){ WVM.setupCarousel(fullVideoId); } }else{ $('#media-container-' + fullVideoId + " " + '.mobile-list-wrapper').slideDown(); $('#media-container-' + fullVideoId + " " + '.page-carousel-wrapper').hide(); if(!$('#media-container-' + fullVideoId).hasClass('floating-video')){ if(!WVM.player_state155200['CAROUSEL_INIT']){ WVM.setupCarousel(fullVideoId); } } } $('#video-slider-nexttitle' + fullVideoId).css('display', 'none'); } }); var currVideoId = WVM['player_state' + fullVideoId]['VIDEO_ID']; //console.log("current Video " + currVideoId); var nextVideoId = WVM.getNextPlaylistIndex(currVideoId); var myTitle = WVM.getPlaylistData(fullVideoId, nextVideoId, 'noprefixtitle'); //console.log("setting title " + myTitle); $('#video-slider-nexttitle' + fullVideoId).css('display', 'inline'); $('#video-slider-nexttitle' + fullVideoId).html(myTitle); }; WVM.sendbeacon = function(action, nonInteraction, value, eventLabel) { var eventCategory = 'Video'; if (window.ga) { //console.log("sending action: " + action + " val: " + value + " label " + eventLabel); ga('send', 'event', { 'eventCategory': eventCategory, 'eventAction': action, 'eventLabel': eventLabel, 'eventValue': value, 'nonInteraction': nonInteraction }); } }; WVM.getNextPlaylistIndex = function(mediaId, returnArrayIndex){ var currId = null; if(mediaId == null){ return null; } for(var x =0; x 20){ if(fullDuration > 1 && ((fullDuration - fullCurrent) > 1) && !$('.vjs-loading-spinner').hasClass('badspinner')){ console.log("hiding spinner"); $('.vjs-loading-spinner').addClass('badspinner'); } } var duration_time = Math.floor(this.duration()); //this is a hack because the end video event is not firing... var current_time = Math.floor(this.currentTime()); if ( current_time > 0 && ( fullCurrent >= (fullDuration - 10) )){ var currId = playerState.VIDEO_ID; var newMediaId = WVM.getNextPlaylistIndex(currId); //if(playerSettings.autoplay_next && newMediaId){ if(newMediaId){ if('desktop' == "iphone" && playerState.AD_ERROR){ console.log("skipped timeupdate end"); }else{ WVM.load_video(newMediaId, true, playerState.ORIGINAL_ID); } } } if(!playerState.START_SENT){ WVM.sendbeacon('start', true, playerState.VIDEO_ID, playerState.VIDEO_TITLE); playerState.START_SENT = true; } var currentTime, duration, percent, percentPlayed, _i; currentTime = Math.round(this.currentTime()); duration = Math.round(this.duration()); percentPlayed = Math.round(currentTime / duration * 100); for (percent = _i = 0; _i = percent && __indexOf.call(playerState['PERCENTS_TRACKED'], percent) 0) { playerState['PERCENTS_TRACKED'].push(percent); } } } }); //player.off('ended'); player.on('ended', function(){ console.log("ended"); playerState.IS_PLAYING = false; WVM.sendbeacon("complete", true, playerState.VIDEO_ID, playerState.VIDEO_TITLE); var currId = playerState.VIDEO_ID; var newMediaId = WVM.getNextPlaylistIndex(currId); //if(playerSettings.autoplay_next && newMediaId){ if(newMediaId){ WVM.load_video(newMediaId, true, playerState.ORIGINAL_ID); }else{ console.log("Playlist complete (no more videos)"); } }); //player.off('adserror'); player.on('adserror', function(e){ //$('#ima-ad-container').remove(); WVM.lastAdRequest = new Date().getTime() / 1000; console.log(e); console.log("ads error"); var errMessage = e['data']['AdError']['l']; playerState.AD_IS_PLAYING = false; playerState.IS_PLAYING = false; // && errMessage == 'The VAST response document is empty.' if(!playerState.AD_ERROR){ var dTime = new Date().getTime(); WVM.firstPrerollTagUrl = WVM.getFirstPrerollUrl(); console.log("calling backup ad tag url: " + WVM.firstPrerollTagUrl); WVM.activePlayer.ima.changeAdTag(WVM.firstPrerollTagUrl + "?" + dTime); WVM.activePlayer.ima.requestAds(); //WVM.activePlayer.src({ // src: masterSrc, // type: 'video/mp4' //}); //WVM.firstPrerollTagUrl = ""; } playerState.AD_ERROR = true; }); //player.off('error'); player.on('error', function(event) { if (player.error().code === 4) { player.error(null); // clear out the old error player.options().sources.shift(); // drop the highest precedence source console.log("now doing src"); console.log(player.options().sources[0]); player.src(player.options().sources[0]); // retry return; } }); //player.off('volumechange'); player.on('volumechange', function(event) { console.log(event); var theHeight = $('#media-container-' + playerState.ORIGINAL_ID + ' .vjs-volume-level').css('height'); var cssVolume = 0; if(theHeight){ cssVolume = parseInt(theHeight.replace('%', '')); } var theVolume = player.volume(); if(theVolume > 0.0 || cssVolume > 0){ $('#media-container-' + playerState.ORIGINAL_ID + ' .mute-overlay').css('display', 'none'); }else{ $('#media-container-' + playerState.ORIGINAL_ID + ' .mute-overlay').css('display', 'block'); } }); WVM.reinitRawEvents(playerState.ORIGINAL_ID); setInterval(function(){ WVM.reinitRawEvents(playerState.ORIGINAL_ID); }, 2000); } if(!WVM.rawCompleteEvent){ WVM.rawCompleteEvent = function(e){ var playerState = WVM['player_state155200']; console.log("firing raw event due to all other events failing"); var currId = playerState.VIDEO_ID; var newMediaId = WVM.getNextPlaylistIndex(currId); //if(playerSettings.autoplay_next && newMediaId){ if(newMediaId){ WVM.load_video(newMediaId, true, playerState.ORIGINAL_ID); } }; } if(!WVM.rawTimeupdateEvent){ WVM.rawTimeupdateEvent = function(e){ var playerState = WVM['player_state155200']; var rawVideoElem = document.getElementById('html5-video-' + playerState['ORIGINAL_ID'] + '_html5_api'); var fullCurrent = rawVideoElem.currentTime * 1000; var fullDuration = rawVideoElem.duration * 1000; var current_time = Math.floor(rawVideoElem.currentTime); console.log("raw timeupdate: " + fullCurrent + " out of " + fullDuration); if ( current_time > 0 && ( fullCurrent >= (fullDuration - 50) )){ var currId = playerState.VIDEO_ID; var newMediaId = WVM.getNextPlaylistIndex(currId); if(newMediaId){ console.log("loading new video from rawtimeupdate"); WVM.load_video(newMediaId, true, playerState.ORIGINAL_ID); } } if(!$('.vjs-loading-spinner').hasClass('badspinner')){ $('.vjs-loading-spinner').addClass('badspinner') } }; } WVM.reinitRawEvents = function(playerId){ var playerState = WVM['player_state' + playerId]; var rawVideoElem = document.getElementById('html5-video-' + WVM['player_state' + playerId]['ORIGINAL_ID'] + '_html5_api'); //COMPLETE EENT if( WVM['player_state' + playerId].COMPLETE_EVENT){ rawVideoElem.removeEventListener('ended', WVM.rawCompleteEvent, false); } rawVideoElem.addEventListener('ended', WVM.rawCompleteEvent, false); //TIME UPDATE EVENT if( WVM['player_state' + playerId].TIMEUPDATE_EVENT){ rawVideoElem.removeEventListener('ended', WVM.rawTimeupdateEvent, false); } rawVideoElem.addEventListener('ended', WVM.rawTimeupdateEvent, false); WVM['player_state' + playerId].COMPLETE_EVENT = true; WVM['player_state' + playerId].TIMEUPDATE_EVENT = true; };

MILWAUKEE (CBS 58) -- A federally published study shows a high level of physical activity is linked with improved vaccine responses in older adults, so could what we eat and how we exercise help improve how our immunity responds to the COVID-19 vaccine?

Experts say its no secret that exercise improves immune function, and they say you dont have to do too much to reap the benefits.

The concept essentially is to simply get your heart rate up higher than if you were sitting down, so that can simply be a brisk walk, says Nicole Kerneen, a registered and certified dietitian and personal trainer at Way of Life Nutrition and Fitness.

Registered dietitians say your immune system will see a boost with consistent light exercise. If you dont exercise regularly but do decide to prior to getting a vaccine, Kerneen says there are still some benefits.

Youll have a lot more circulation happening, you also have all of the immune receptors really alert, and so that in turn can essentially help, she adds.

Experts say some sort of upper body movement after getting a vaccine isnt a bad idea either.

Post-vaccination, if youre able to and feeling well enough of course, without stressing the body too much, engage in some light activity. That can actually promote circulation which can support our immune systems response said Cassie Vanderwall, a clinical nutritionist at UW Health.

As simple as with no weight at all and youre just moving your arm up and down, youre stretching it and allowing it to move, Kerneen adds.

Vanderwall says certain foods can also cause inflammation, which affects immune response.

High sugary processed foods, those are pro-inflammatory, meaning theyre going to light the fire, were actually looking for foods that are going to put out or calm down the fire, she says.

Kerneen says when it comes to improving immunity with food, consistency is key, but eating something unhealthy every once in a while is still okay. Dieticians suggest foods like leafy green vegetables, berries, citrus, garlic and onions.

Those things are incredible for your body and for your immune system and to decrease inflammation, says Kerneen.

Salmon or walnuts, nuts and seeds. A meal composed of those items post-vaccine, pre-vaccine or every day is really going to help, Vanderwall said.

On top of diet and exercise, experts say good rest and hydration can also provide good circulation before and after you get a COVID-19 vaccine.

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Experts say healthy diet and light exercise may boost immune response to the COVID-19 vaccine - WDJT

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Insights into how COVID outsmarts the gut’s immune response could point to new treatments – FierceBiotech

Sunday, May 2nd, 2021

Scientists studying SARS-CoV-2, the virus behind COVID-19, have known since the early days of the pandemic that it can infect the stomach. But how the gut mounts an immune response to the virus is still largely a mystery.

A team from the European Molecular Biology Laboratory (EMBL) used live models of the human gut to study how intestinal cells respond to COVID-19and what they learned could inform efforts to develop new therapies, they said.

The researchers discovered that SARS-CoV-2 disrupts interferon signaling in certain gut cells to cause an inflammatory immune response to the virus. They described their findings in the journal Molecular Systems Biology.

RELATED: Gut bacteria point to novel strategies for combating asthma, COVID-19

The EMBL team started by creating 3D tissue models, or organoids, of the human gut. The models allowed them to determine that a particular subpopulation of cells called enterocytes are most affected by SARS-CoV-2.

They used single-cell RNA sequencing to track cell activity as the disease progressed, observing how the enterocytes triggered a response from the immune system by scrutinizing the activity of 12 genes.

The researchers were surprised to discover that the enterocytes most affected by the virus did not display high levels of ACE2, a cell-surface receptor that has previously been fingered as a culprit in causing COVID-19 infection. Furthermore, they found that infected gut cells mounted a pro-inflammatory response to the virus by pumping up levels of the transcription factor NFkB and the cytokine TNF.

Interferon-stimulated genes were only dialed up in bystander cells, suggesting COVID-infected cells were actively blocking interferon signaling, the EMBL researchers concluded.

The guts role in respiratory diseases has piqued the interest of other research teams, including one at Monash University in Australia. Researchers there suggested earlier this year that L-tyrosine metabolized by gut microbes might shield the lungs from inflammation. They demonstrated that over-the-counter L-tyrosine supplements were effective in mouse models of acute respiratory distress syndrome, which can occur in severe cases of COVID-19.

The variety of immune responses that the EMBL researchers found among different cells of the gut suggest that there are cell type-specific or tissue-specific regulations of interferon-mediated signaling during SARS-CoV-2 infection, they wrote in the study. This needs to be considered when studying replication and pathogenesis of SARS-CoV-2 in different organs as well as when developing therapies against COVID-19.

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Insights into how COVID outsmarts the gut's immune response could point to new treatments - FierceBiotech

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How can you improve your immune system in the second wave of COVID? – The Bridge

Sunday, May 2nd, 2021

A high immunity is always credited for various reasons such as a good diet, exercise, minimal health complications, etc. The benefits of having a functional and stable immune system are phenomenal with the most prominent one being the prevention of diseases and infections. The harmful short and long-term effects of Covid 19 cannot be stressed enough and by now it is evident that there need to be proactive countermeasures to deal with the same. Here are some tips and tricks to ramp up the functioning of an immune system of a person with basic self-care measures

A balanced diet is one of the best possible ways of fighting infections. Food items such as vegetables, fruits, pulses, meat, milk products all have the necessary nutritional requirements for the body to counter certain viral infections that may be sourced externally. It is not necessary to have high protein or high fat (or any particular nutrient) but it should be a combination of everything that the body is receptive towards in a normal course of life.

While many might consider this to be a mental aspect of immunity, the phrase 'healthy mind, healthy body' is true. Stress levels have been found to directly contribute to aggravating an infection or disease in a body simply due to lack of adequate care or ignorance of symptoms. It might be easier said than done but activities like meditation, cooking, exercising, carrying out hobbies, etc are all big stress relievers.

The impact of Covid 19 during the second wave has been disastrous, to say the least. Breathing exercises, drinking warm water frequently, taking care of a person's physical and mental health are just a few more ways of ensuring that there is adequate immunity. Immunity booster medication too might help as an external means but for one to truly help the body be physically and mentally ready, it is necessary to be consistent with the physical and mental requirements on a day-to-day basis.

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How can you improve your immune system in the second wave of COVID? - The Bridge

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Pfizer vs. Moderna Vaccines: Does One Have More Side Effects Than the Other? – NBC Chicago

Sunday, May 2nd, 2021

As many continue receiving their first or second doses of the Pfizer and Moderna COVID vaccines currently available, what are the potential side effects and does one cause more side effects than the other?

Chicago Department of Public Health Commissioner Dr. Allison Arwady was recently asked that very question.

There have also been reports of potential symptoms like "COVID arm" or changes in menstrual cycles.

Here's what we know so far about the two mRNA vaccines and their side effects:

Side effects are possible after receiving any COVID vaccine currently being administered in the U.S.

Experiencing side effects isn't necessarily a bad thing. In fact, it's a sign your body is responding.

"That's just your immune system learning the lesson of how to fight it off," Chicago's top doctor said in a Facebook Live Tuesday. "So people who have stronger side effects, it's just a sign that you have a very robust strong immune system that's learning the lesson."

The CDC reports the most common side effects for the vaccines is at the injection site. They include:

Common side effects in the body include:

The Centers for Disease Control and Prevention advises people to stick around for 15 minutes after vaccination, and those with a history of other allergies for 30 minutes, so they can be monitored and treated immediately if they have a reaction.

Recent reports have brought to light some other unexpected but so far not serious side effects that could be related to the vaccines, experts say.

As more and more Americans receive their first or second doses of the Pfizer or Moderna COVID vaccines every single day, some people who menstruate are reporting changes to their periods after getting vaccinated.

Dr. Kate Clancy, an associate professor of anthropology at the University of Illinois, posted her experience on Twitter in February and received hundreds of reports from those experiencing what she pondered could be a little-publicized response to the two available mRNAvaccines.

Chicago Department of Public Health Commissioner Dr. Allison Arwady was asked about the possibility of vaccinations impacting menstruation in a Facebook live broadcast last week.

"Two hundred and twenty million Americans have gotten a first dose of vaccine, right? So, among 220 million Americans, there are people who will have, you know a herpes outbreak, who will have a changed menstruation cycle, etc.," she said. "What has been interesting, I think, is that, that this has really raised some awareness for wanting to make sure that we're asking questions about things like changes in menstruation, right? Most vaccine trials, most trials in general actually, unless they're really focused on women's reproductive health, may not even ask questions like that and that perhaps points to some biases in terms of how, you know, trials in general for medications, etc. are set up."

"I have not seen anything, to be very clear, that suggests that there is any concerning side effects in the way that would last, I know and there's a local researcher who is looking at some of this related menstruation, but very clear there's not been any link to, you know, problems with fertility, you know, anything that's long-lasting but, you know, the goal of getting a vaccine is for your immune system to learn how to protect yourself against COVID and your immune system can interact, can interface with your, you know, your hormonal levels, etc. and so there is at least some biological plausibility that you could have, you know, some change in terms of a heavier period or a lighter period for example right after getting the vaccination," Arwady continued.

Health experts have noted that menstrual changes have been documented in recent months outside of vaccinations as well.

Dr. Whitney Lyn, a Family Medicine attendee for Cook County Health, acknowledged the possibility of changes post-vaccination, but also noted that stress can also play a role in a woman's cycle.

"Women's menstrual cycle can, you know, always change month to month for various reasons," Lyn said. "And so one of the things that causes a woman's menstrual just to change is stress and so right now we're seeing a very stressful time. And so every time someone gets the vaccine, they're a little stressed out, so sometimes can that make your flow a little heavier or a little lighter? Yes. And so, I think it's a normal response, but I don't think it's a reason not to take the vaccine."

Even without contracting COVID or getting vaccinated, menstrual changes have been reported possibly stemming from the overall pandemic environment itself. AWashington Post report from Augustfound that several gynecologists "confirmed that many of their patients are reporting skipped periods or have noticed increases or decreases in cycle length, blood volume and level of menstrual-related pain."

There have also been reports of what's known as "COVID arm," a term used to describe delayed skin reactions such as rashes, which appear days after injection.

"If it is going to arise, it usually appears about a week after your vaccine,Dr. Brita Roy, an internal medicine physician and director of population health for Yale Medicine said. Its a red, swollen area at the site of the shot."

The skin reactions gained attention when a letter was published in theNew England Journal of Medicineearlier this month detailing some patients who experienced varying degrees of arm rashes following their first dose of the Moderna vaccine.

Its not super common, but its not uncommon. Its a delayed hypersensitivity, similar to what you may see if you get poison ivy, Roy said. You maybe came into contact with the poison ivy in your yard, but some people wont get a rash until a few days later.

The Centers for Disease Control and Prevention has acknowledged reports "that some people have experienced a red, itchy, swollen, or painful rash where they got the shot," which it identified as "COVID arm."

According to theCDC, the rashes can start within a few days to more than a week after the first shot and "are sometimes quite large."

"If you experience 'COVID arm' after getting the first shot,you should still get the second shotat the recommended interval if the vaccine you got needs a second shot," the CDC noted. "Tell your vaccination provider that you experienced a rash or 'COVID arm' after the first shot. Your vaccination provider may recommend that you get the second shot in the opposite arm."

The CDC said those who experience COVID arm can take an antihistamine.

"If it is painful, you can take a pain medication like acetaminophen or a non-steroidal anti-inflammatory drug (NSAID)," the CDC recommends.

According to Pfizer, about 3.8% of their clinical trial participants experienced fatigue as a side effect and 2% got a headache.

Moderna says 9.7% of their participants felt fatigued and 4.5% got a headache.

But experts say data shows the two are similar and that side effects depend more on the person than shot itself.

"I would not try to make a decision between one, you know, between Moderna and Pfizer in particular, based on side effects," Arwady said Tuesday. "I think get the one that's available to you and do definitely get that second dose."

With the two-shot vaccines, people are more likely to report side effects after their second dose, experts have said.

According to the CDC, side effects after your second shot "may be more intense than the ones you experienced after your first shot."

"These side effects are normal signs that your body is building protection and should go away within a few days," the CDC states.

In trials of both the Moderna and Pfizer vaccines, more people experienced side effects after the second dose.

Arwady noted that a good indicator of whether you'll experience side effects after your second dose is how your body reacted to the first.

"The biggest predictor between first and second doses is what your own reaction was," she said. "So if you didn't have much of a reaction after the first dose, you're unlikely to have a big reaction after the second dose. We do see people having a little more side effects after the second dose than the first but usually not a huge, huge amount of difference."

She added that Johnson & Johnson's vaccine "does have a lower rate of the side effects in those first few days than the other two do."

But that doesn't mean that you shouldn't get your second shot if you get side effects after your first, experts say.

When people receive that second dose, they are receiving the second booster to try and reach the maximum efficacy," said Dr. Edward Cachay, infectious disease specialist at UCSD.

The CDC also noted that both shots are needed.

"ThePfizer-BioNTech COVID-19 VaccineandModerna COVID-19 Vaccineboth need 2 shotsin order to get the most protection," the CDC states. "You should get the second shot even if you have side effects after the first shot, unless a vaccination provider or your doctor tells younot to get it."

There are also some factors that could make you more likely to experience side effects.

Chicago's top doctor said Tuesday that the biggest predictor for side effects so far has been age.

"Older people, broadly, do not have as much side effects and that's because their immune systems are not quite as robust, generally and so they don't mount as much of a immune response," Arwady said. "It doesn't mean that they're not protected."

According to Loafman, the body's immune system is what creates the symptoms.

"That's simply a reflection of the immune response, just the way we have when we get ill," he said.

Arwady also noted that women are more likely to report side effects than men.

"Some of this is because women may just be better reporters... but there probably is something real to this too because something else interesting for those who may not know as much about immunity is that autoimmune diseases? Much, more likely in women, too," Arwady said. "And even the, like, more serious like the allergic reactions, the more serious allergic reactions? More likely in women."

Why is that?

Arwady said estrogen can elevate immune responses, while testosterone can decrease it. At the same time, she noted that "a lot of your immune modulating genes" can live on an "x" chromosome, which women have two of, while men have one.

"So there's all these reasons that sort of immunity in general goes up a little bit different in women than it does in men," she said. "And so we're seeing women, a little more likely to report some of the side effects."

Data from the CDC also reported women were more likely to experience side effects than men, according monitoring from the first month of vaccinations.

From Dec. 14 through Jan. 13, more than 79 percent of side effects were reported by women, the data showed. Meanwhile, women received roughly 61.2 percent of the doses administered during that same time.

Side effects could also vary depending on whether or not you've had coronavirus.

"We have seen more likely that people will report some side effects because that is acting a little bit like a booster dose to your immune system," Arwady said. "Your immune system has already learned some of those lessons of how to protect itself, not in as long a way not as protective a way."

"That is also probably that booster effect," Arwady said.

Loafman agrees.

"If you had COVID a while ago or you've already got some immunity, it's more like a booster," he said. "And boosters for some people are completely asymptomatic, boosters for other people trigger their immune response against it so they have some inflammation with it."

But not getting side effects isn't a negative, health experts say.

"If you don't get side effects it does not mean that you are not protected," Arwady said. "I want to be really clear about that."

According to Loafman, it simply means "your body didn't react with as much of an inflammatory response.

"You're still making antibodies," he said.

According to Loafman, every person's response is unique.

"It's really just kind of a reflection of how unique each of our systems are, what other immunities we have," he said. "You know, a lot of the antibodies cross react and we have cross reactivity so it's really a mosaic. Each of our immune systems is a mosaic composite of all that we've been through and all that we have and all we've recently been dealing with. Our individual response varies. Everybody gets gets the appropriate immune response."

Questions about vaccine effectiveness have been paired with a rise in spread of multiple COVID variants.

So far, studies suggest that the vaccines currently in use can recognize the emerging variants but theymay not provide as much protectionagainst the new strains.

Pfizer's latest study results, however, suggested that the vaccine is effective against the coronavirus variant that first emerged in South Africa.

These data also provide the first clinical results that a vaccine can effectively protect against currently circulating variants, a critical factor to reach herd immunity and end this pandemic for the global population," Ugur Sahin, CEO and co-founder of BioNTech, said in a statement.

Moderna, citing data from its phase three clinic trial, reported its COVID-19 vaccine was more than 90% effective at protecting against COVID and more than 95% effective against severe disease up to six months after the second dose, the company said.

But boosters and new versions of vaccines that target the variants are already being explored.

Pfizer-BioNTech is testing a third booster shotof its vaccine on fully vaccinated people. PfizerCEO Albert Bourla said people will "likely" need a third dose of a COVID-19 vaccine within 12 months of getting fully vaccinated.

"The flexibility of our proprietary mRNA vaccine platform allows us to technically develop booster vaccines within weeks, if needed," Ugur Sahin, CEO and co-founder of BioNTech, said in arelease.

Late last month, the National Institutes of Health started testing a new COVID vaccine from Moderna aimed at protecting against a variant first discovered in South Africa. Moderna CEO Stephane Bancel told CNBC that the companyhopes to have a booster shotfor its two-dose vaccine available in the fall.

But what about without the variants?

In clinical trials,Moderna's vaccine reported 94.1% effectivenessat preventing COVID-19 in people who received both doses. ThePfizer-BioNTech vaccinewas said to be 95% effective.

A new CDC study reported that a single dose of Pfizer's or Moderna's COVID vaccine was 80% effective in preventing infections. That number jumped to 90% two weeks after the second dose, the study on vaccinated health care workers showed.

"These findings indicate that authorized mRNA COVID-19 vaccines are effective for preventing SARS-CoV-2 infection, regardless of symptom status, among working-age adults in real-world conditions," the U.S. agency wrote in the study. "COVID-19 vaccination is recommended for all eligible persons."

It is not known if any of the vaccines prevent the spread of the virus by people who are asymptomatic.

Monica Hendrickson, public health administrator for the Peoria County Health Department noted that the vaccines each hold a high effectiveness against death and severe illness for coronavirus.

"So, really, you're looking at a distinction that from a clinical standpoint, or from, you know, an epidemiological standpoint is very minor compared to what we really are hoping for, which is decreases in death and decreases in severe illness, where they all match up between the three vaccines," Hendrickson said. "Most important thing though is that when these vaccines come on the market, if you have an option to any of these, get one of them."

Hendrickson's message echoes one made by Dr. Marina Del Rios, emergency medicine specialist at the University of Illinois-Chicago,during NBC 5's "Vaccinated State" panel.

Part of my messaging in the community has been that the vaccines on the market are equally efficacious and equally safe," Del Rios said. "The best vaccine you can get is the one that you can get ahold of first, and getting vaccinated earlier, sooner rather than later, protects us from getting sick ourselves and also our community, which has been so terribly devastated by this virus.

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Pfizer vs. Moderna Vaccines: Does One Have More Side Effects Than the Other? - NBC Chicago

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Family Healthcast: can alcohol consumption reduce your immunity to COVID? – WSYR

Sunday, May 2nd, 2021

Posted: Apr 30, 2021 / 06:14 PM EDT / Updated: Apr 30, 2021 / 06:15 PM EDT

FAMILY HEALTHCAST After a long year and a lot of anticipation, getting the COVID-19 vaccine can be cause for celebration, which for some might mean pouring a drink and toasting to their new immunity. But can alcohol interfere with your immune response?

The short answer is that it depends on how much you drink. Heavy alcohol consumption, particularly over the long term, can suppress the immune system and potentially interfere with your vaccine response according to experts.

Since it can take weeks after a COVID shot for the body to generate protective levels of antibodies against the virus, anything that interferes with the immune response would be cause for concern.

There is no evidence that moderate drinking around or after being vaccinated makes the shots less effective. Some studies have even found that over the longer term, small or moderate amounts of alcohol might actually benefit the immune system by reducing inflammation.

Moderate drinking is generally defined as no more than two drinks a day for men and a maximum of one drink a day for women, whereas heavy drinking is defined as four or more drinks for men and three for women.

Another reason to moderate your alcohol intake is that heavy drinking, along with the hangover that might ensue, can potentially amplify any side effects you might have from the COVID vaccine, including fever, fatigue or body aches.

However, doctors say having a glass of champagne probably wont inhibit any immune response, celebratory alcoholic beverages in moderation are fine.

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‘Smart’ immune cells kill tumours and stop them regrowing in mice – New Scientist News

Sunday, May 2nd, 2021

By Michael Le Page

A person having blood drawn for CAR-T therapy

GERARD JULIEN/AFP via Getty Images

Immune cells programmed to attack tumours in a smarter way have shrunk brain and ovarian tumours in mice studies where unaltered immune cells failed. The technology could be used to treat cancers as well as degenerative brain disorders.

We have more control over what the cell does when it reaches the disease site, says Kole Roybal at the University of California, San Francisco. We can really program in very specific functions.

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Our bodies naturally kill off many nascent cancers, but sometimes immune cells called T-cells dont recognise cancerous cells. One way to treat cancers that manage to dodge the immune system is to genetically engineer T-cells to produce a receptor that helps them target a specific protein on thecancer cells surface. These are called CAR T-cells, where CAR stands for chimeric antigen receptor.

CAR-T therapies have cured a few people, leading the US to approve two forms in 2017. But there are major limitations. The approach has only been effective against blood cancers such as leukaemia, not against solid tumours. And it can have very serious even fatal side effects if the T-cells kill off non-cancerous cells that also have the target protein on their surface.

These problems are related. One of the reasons why CAR-T therapies dont work for solid tumours is that not all cells in such tumours express a single, unique protein, says Roybal. So his team has developed a new type of receptor protein that works in a different way. Instead of triggering an instant attack, these T-cell receptors switch on any desired gene or genes when they recognise a target protein. This can be any protein the researchers choose, which is why the technique can be used for brain disorders in addition to cancers.

Roybals team engineered this receptor to recognise a protein specific to some cells in brain tumours called glioblastomas. The receptor then activated a gene for a standard CAR-T receptor that targets a protein found on a wider range of tumour cells and on healthy cells. Crucially, though, the killing effect was limited to tumour environments where both proteins are present: if the engineered cells leave the tumour, the CAR-T gene gets switched off again.

In tests in mice, this approach shrunk glioblastomas and prevented recurrence where conventional CAR-T therapies either didnt work or didnt prevent regrowth. In a separate animal study, similar results were found for ovarian cancers and mesotheliomas, which are mostly caused by asbestos.

Standard CAR T-cells seem to become exhausted relatively quickly and die off, says Roybal. The smart CAR T-cells persisted for longer in the body, which is important for preventing recurrence, he says.

We are solving a load of the roadblocks in solid tumours, says Roybal. We are not all the way there, theres a lot of work to do, but we have taken major steps.

For instance, tumours often release factors that suppress an immune response. His team plans to engineer the smart CAR-T cells to release other factors that counteract this, and stimulate a broader immune response against tumours.

His team is also getting the therapies used in the mice ready for human trials, which could take a couple of years. These trials will involve removing a patients immune cells and genetically engineering them before putting them back in the body. In the longer term, it may be possible to treat people using off-the-shelf cells, which would greatly reduce costs.

Journal References: Science Translational Medicine, DOI: 10.1126/scitranslmed.abe7378 & 10.1126/scitranslmed.abd8836

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We clarified which type of tumours were shrunk by the immune cells

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Seven supplements to support your immune system – The Tri-City News

Sunday, May 2nd, 2021

When it comes to keeping your immune system strong to fight off colds and flu, certain supplements can give your body the boost it needs

Staying healthy is at the top of everyones minds these days.

Fortunately, Popeyes Supplements in Coquitlam and Burnaby offer a welcoming environment for anyone interested in supporting their health.

We pride ourselves on outstanding customer service, owner Brad Alderson says.

We have the best selection of all the top brand name supplements and vitamins in Canada at the lowest prices. We strive to help our customers exceed their health and fitness goals.

When it comes to keeping your immune system strong to fight off colds and flu, certain supplements can give your body the boost it needs.

Alderson recommends the following seven supplements to support your immune system, all available in-store at Popeyes, and on thewebsite.

VegeGreens is a comprehensive combination of over 60 land, sea, and cruciferous vegetables as well as super green food, herbal extracts and botanicals. Each small scoop provides the nutrient equivalent of six to eight servings of fresh vegetables.

This supplement helps increase energy and renew mental clarity, cleanse your body, strengthen immune function, and balance your pH. It also supports your heart, liver and digestive health.

PhytoBerry is a highly concentrated berry-based whole food supplement thats loaded with natural antioxidants. Featuring over 40 fruit concentrates, PhytoBerry is specifically designed to offer whole body antioxidant protection. A single serving has the equivalent nutrient content of six to eight servings of fresh fruit.

This supplement supports immune functions, provides antioxidant protection for your entire body, and increases energy.

Dont overlook the power of vitamins when it comes to boosting your immune system. Progressive Vitamin D3 can help with the maintenance of good health.

Vitamin D3 provides immune system support, promotes the development of healthy bones and teeth, and helps the body absorb calcium.

Progressive Vitamin C Complex provides isolated sources of vitamin C for increased potency. The plant-based digestive support of papaya and black pepper extract increase the absorption and maximize the health-promoting properties of the entire formula.

The Vitamin C Complex provides powerful antioxidant protection, supports cardiovascular health and immune function, and promotes healthy bones, joints, teeth, and gums.

Precision All Natural Whey Isolate features a gently processed, low-temperature filtered whey protein isolate imported from New Zealand. New Zealand proteins are considered to be the cleanest in the world. The cattle there are raised without the use of growth-regulating steroids or milk-inducing hormones (including rBGH). Also, the milk supply is routinely screened for over 200 agricultural and chemical contaminants.

This form of New Zealand isolate is an excellent source of dietary protein and will help build muscle and repair lean body tissue. It is anabolic and gluten free, low in fat and cholesterol, and provides a broad range of amino acids.

Precision All Natural Whey Isolate tastes great and easily blends into a rich and creamy high protein shake or smoothie. Its the perfect choice for people with active lifestyles or for anyone wishing to increase their protein intake while avoiding artificial ingredients.

Medicinal mushrooms have a history of use in traditional medicine stretching back thousands of years. Each mushroom offers its own nutritional profile and therapeutic potential.

Mushrooms help increase energy and support resistance to stress. Mushrooms are also used to support the immune system.

Probiotics are helpful bacteria that keep your gut healthy. They support intestinal health and help with digestive challenges.

Alderson recommends two products Popeyes offers:

Perfect Probiotic Colon Support, part of the worlds first TRU-ID Certified probiotic family which guarantees every species listed on the label is included in every capsule.

The other option is Perfect Probiotic 60 Billion, an extra-strength probiotic for daily use and supports intestinal health when you feel off.

To learn more and to order the best deals on nutritional supplements online, visit http://www.popeyesbc.ca.

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You Don’t Have to Suffer to Benefit From COVID Vaccination But Some Prefer It – HealthLeaders Media

Sunday, May 2nd, 2021

This article was published on Wednesday, April 28, 2021 in Kaiser Health News.

By Arthur Allen

If you think vaccination is an ordeal now, consider the 18th-century version. After having pus from a smallpox boil scratched into your arm, you would be subject to three weeks of fever, sweats, chills, bleeding and purging with dangerous medicines, accompanied by hymns, prayers and hell-fire sermons by dour preachers.

That was smallpox vaccination, back then. The process generally worked and was preferred to enduring "natural" smallpox, which killed around a third of those who got it. Patients were often grateful for trial-by-immunization once it was over, anyway.

"Thus through the Mercy of God, I have been preserved through the Distemper of the Small Pox," wrote one Peter Thatcher in 1764, after undergoing the process in a Boston inoculation hospital. "Many and heinous have been my sins, but I hope they will be washed away."

Today, Americans are once again surprisingly willing, even eager, to suffer a little for the reward of immunity from a virus that has turned the world upside down.

Roughly half of those vaccinated with the Moderna or Pfizer-BioNTech vaccines, and in particular women, experience unpleasantness, from hot, sore arms to chills, headache, fever and exhaustion. Sometimes they boast about the symptoms. They often welcome them.

Suspicion about what was in the shots grew in the mind of Patricia Mandatori, an Argentine immigrant in Los Angeles, when she hardly felt the needle going in after her first dose of the Moderna vaccine at a March appointment.

A day later, though, with satisfaction, she "felt like a truck hit me," Mandatori said. "When I started to feel rotten I said, 'Yay, I got the vaccination.' I was happy. I felt relieved."

While the symptoms show your immune system is responding to the vaccine in a way that will protect against disease, evidence from clinical trials showed that people with few or no symptoms were also protected. Don't feel bad if you don't feel bad, the experts say.

"This is the first vaccine in history where anyone has ever complained about not having symptoms," said immunologist Dr. Paul Offit, director of the Vaccine Education Center at Children's Hospital of Philadelphia.

To be sure, there is some evidence of stronger immune response in younger people and in those who get sick when vaccinated. A small study at the University of Pennsylvania showed that people who reported systemic side effects such as fever, chills and headache may have had somewhat higher levels of antibodies. The large trial for Pfizer's vaccine showed the same trend in younger patients.

But that doesn't mean people who don't react to the vaccine severely are less protected, said Dr. Joanna Schaenman, an expert on infectious diseases and the immunology of aging at the David Geffen School of Medicine at UCLA. While the symptoms of illness are undoubtedly part of the immune response, the immune response that counts is protection, she said. "That is preserved across age groups and likely to be independent of whether you had local or systemic side effects or not."

The immune system responses that produce post-vaccination symptoms are thought to be triggered by proteins called toll-like receptors, which reside on certain immune cells. These receptors are less functional in older people, who are also likely to have chronic, low-grade activation of their immune systems that paradoxically mutes the more rapid response to a vaccine.

But other parts of their immune systems are responding more gradually to the vaccine by creating the specific types of cells needed to protect against the coronavirus. These are the so-called memory B cells, which make antibodies to attack the virus, and "killer T cells" that track and destroy virus-infected cells.

Many other vaccines, including those that prevent hepatitis B and bacterial pneumonia, are highly effective while having relatively mild side effect profiles, Schaenman noted.

Whether you have a strong reaction to the vaccine "is an interesting but, in a sense, not vital question," said Dr. William Schaffner, a professor of infectious disease at Vanderbilt University Medical Center. The bottom line, he said: "Don't worry about it."

There was a time when doctors prescribed cod-liver oil and people thought medicine had to taste bad to be effective. People who get sick after COVID vaccination "feel like we've had a tiny bit of suffering, we've girded our loins against the real thing," said Schaenman (who had a slight fever). "When people don't have the side effects, they feel they've been robbed" of the experience.

Still, side effects can be a hopeful sign, especially when they end, says McCarty Memorial Christian Church leader Eddie Anderson, who has led efforts to vaccinate Black churchgoers in Los Angeles. He helps them through the rocky period by reminding them of the joyful reunions with children and grandchildren that will be possible post-vaccination.

"I'm a Christian pastor,'' he said. "I tell them, 'If you make it through the pain and discomfort, healing is on the other side. You can be fully human again.'"

This story was produced byKHN, which publishesCalifornia Healthline, an editorially independent service of theCalifornia Health Care Foundation.

Arthur Allen: ArthurA@kff.org, @ArthurAllen202

Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.

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Vaccines do provide immunity and can be used to achieve herd immunity – Health Feedback

Sunday, May 2nd, 2021

CLAIM

Vaccines dont promise immunity and therefore vaccine herd immunity doesnt exist.

DETAILS

Inaccurate: Contrary to the claim, vaccines, which train a persons immune system to respond to pathogens, provide immunity and are the safest strategy for achieving herd immunity. Natural infection also provides immunity, but achieving herd immunity through infection would result in unnecessary cases of the disease and deaths.

KEY TAKE AWAY

Herd immunity occurs when a significant portion of a population is immune to a pathogen, making it difficult for the pathogen to spread through the population. Apart from protecting vaccinated individuals, herd immunity provides indirect protection from infection even to individuals who are unable to be vaccinated. One strategy to achieve herd immunity is through vaccination, which provides protective immunity to vaccinated individuals.

REVIEW As COVID-19 vaccination campaigns move forward in a number of countries, journalists, healthcare professionals and scientists have raised the questions of when a country can expect to reach herd immunity and if they are close to reaching it.

Herd immunity is a concept that describes the point at which the population as a whole is protected from an infectious disease. This point occurs when enough people in a population or herd are protected from that disease, either through vaccination or through previous infection. This in turn protects even individuals susceptible to the disease, because they are a member of a herd where the majority are protected, making it unlikely for the susceptible individual to become infected.

To better understand the concept of herd immunity, picture 100 people in a room. When a new infectious disease appears, everyone is susceptible to the disease and each person, once infected, has the potential to spread that disease to their neighbors. However, if a large percentage of the population is immune, even if the disease infects one of the few susceptible individuals, the pathogen will have a hard time spreading because the majority is protected. When this is achieved, the population is considered to have herd immunity.

In an Instagram post published on 24 April 2021, Laura Elizabeth claimed that herd immunity from vaccines doesnt exist and provided four explanations for her claim. The post received over 7,000 likes and 200 comments as of 30 April 2021. As we demonstrate below, this claim is inaccurate, as are all four explanations given by Elizabeth.

Figure Screenshot of Laura Elizabeths post about vaccine herd immunity. On the left is her claim, and on the right are the four inaccurate reasons to explain her claim.

Elizabeth claimed that 100 percent of the population would have to be vaccinated to achieve herd immunity. However, in several cases, herd immunity can be achieved even when less than 100% of the population is vaccinated. The more infectious a disease is, the higher the proportion of the population that has to be protected before we get to herd immunity, explained epidemiologist Gypsyamber DSouza, a professor at the Johns Hopkins Bloomberg School of Public Health, in a video released by Johns Hopkins.

For a highly infectious disease like measles, where each infected person on average transmits the virus to between 12 to 18 other individuals, at least 95% of the population must be vaccinated to achieve herd immunity. For a less infectious disease like polio, the necessary threshold of vaccinated individuals is about 80%. The vaccine threshold for COVID-19 is still a matter of debate, but recent estimates range from 70 to 90 percent.

In short, herd immunity requires that a sufficiently high percentage of the population be protected, so that it is difficult for the infectious disease to spread through the population. But that percentage varies greatly depending on the characteristics of the disease, especially how infectious it is. Hence, Elizabeths claim that 100 percent of the population would have to be vaccinated for herd immunity to be achieved is inaccurate.

The immune system is a complex network of cells, tissues, organs, and the substances they make that helps the body fight infections and other diseases, according to the U.S. National Cancer Institute. When a persons immune system recognizes an invading pathogen for the first time, the system begins to address the problem. White blood cells converge on the site of the infection, while antibodies that specifically target that pathogen are produced. It can take several days for antibodies to develop and, in the meantime, the infected individual may become ill. Following this first exposure, however, the immune system will remember this pathogen and more quickly mount an immune response when it encounters the pathogen again.

Vaccines work by providing a persons immune system with a sneak peek of a pathogen. This sneak peek involves a weakened or inactive part of the pathogen, which allows the vaccinated persons immune system to create antibodies against the pathogen and avoid the risks of an actual infection. When an individual is exposed to a pathogen theyre vaccinated for, their immune system can quickly respond to it.

In her Instagram post, Elizabeth claimed that vaccines dont promise immunity. That is inaccurate. Immunity is the ability of the body to resist a particular disease, and that is exactly what vaccines are designed to provide. By giving a sneak peek of a pathogen, vaccines allow an individual to swiftly mount an immune response when they encounter the pathogen in the future.

Elizabeth also inaccurately claims that a great deal of people dont become immune after getting the vaccine. No vaccine is 100% effective, which is why some individuals may still get infected after theyve been vaccinated. But the percentage of individuals who do not generate immunity following vaccination is small. For instance, about one percent of people who receive both doses of the Measles, Mumps, Rubella (MMR) vaccine dont develop protective immunity.

In her post, Elizabeth claimed that immunity from vaccines is temporary. This is inaccurate because the duration of immunity generated by both vaccines and natural infection varies for different pathogens. For instance, people who receive two doses of the MMR vaccine are considered to have lifelong immunity for both measles and rubella. However, immunity to mumps decreases over time, which is why the CDC recommends a booster shot of the MMR vaccine during mumps outbreaks. In general, vaccine boosters are recommended because of waning immunity.

Elizabeth also implied that natural immunity is lifelong and therefore superior to vaccine immunity. This isnt the case, because infection with the pathogen can generate a dramatic range of immune responses. In the case of COVID-19, for instance, as many as 9% of recovered people have no detectable antibodies, although many who survive the disease develop immunity that may persist for years. Furthermore, those with a mild illness from COVID-19 may see their immunity wane after a few months.

One possible reason for individual variation in immunity following infection is that individuals are exposed to different amounts of the virus. With vaccines, however, everyone receives a similar dose that is known to be effective at generating an immune response. In a piece for The Conversation, immunologist Jennifer Grier, an assistant professor at the University of South Carolina, explained that COVID19 vaccines offer safer and more reliable immunity than natural infection, because immunity following natural infection can be unpredictable. As detailed in a previous Health Feedback review, vaccines also allow individuals to gain immunity without the risks associated with natural infection.

There are a few vaccine technologies that are commonly used. The classical types are inactivated, live-attenuated, and subunit vaccine designs. With the COVID-19 vaccines, two new designs have been added to the repertoire: mRNA and viral vector vaccines.

Inactivated vaccines use a killed version of the pathogen to confer immunity. Examples of inactivated vaccines include the flu, polio, Hepatitis A and rabies vaccines. Live-attenuated vaccines use an attenuated or weakened version of the pathogen, which is unable to cause disease, to generate immunity. Examples of live-attenuated vaccines include the MMR, rotavirus, smallpox, chickenpox and yellow fever vaccines.

Subunit vaccines use only a component from the pathogen, like a protein, to confer immunity. The Hepatitis B, human papillomavirus, whooping cough, pneumococcal, meningococcal, and shingles vaccines are examples of subunit vaccines.

Among the COVID-19 vaccines are mRNA and viral vector vaccines, two designs that deliver information to cells on how to produce a pathogens protein. These proteins then trigger the immune response, generating immunity.

In her post, Elizabeth claimed that all live virus vaccines shed. Vaccine shedding is the idea that vaccinated individuals will release or shed viruses into the population. Because most vaccine design strategies use a killed pathogen or only part of a pathogen, none of these types of vaccines can lead to vaccine shedding. In her post, Elizabeth writes that the shingles vaccine sheds, however, the shingles vaccine is a subunit vaccine and cant cause vaccine shedding.

Because they contain a weakened version of the pathogen, live-attenuated vaccines have the potential to shed live viruses. However, whats being shed is the weakened version of the pathogen used in the vaccine, which doesnt make people sick. One example of a vaccine that causes shedding is the smallpox vaccine, which helped eradicate the disease and is no longer routinely administered. For this vaccine, shedding could happen at the site of injection up to 19 days. The oral poliovirus (OPV) vaccine also leads to shedding of the weakened poliovirus in up to 90% of infants [1]. Some countries have swapped the OPV for the inactivated poliovirus (IPV) vaccine, which doesnt shed, because in rare occasions the shed vaccine virus may mutate and cause polio.

Of the routine vaccines given, both the rotavirus and chickenpox vaccines do shed, but in both cases infection is unlikely. For rotavirus, the vaccinevirus is shed in the stool and proper hygiene, such as hand washing, can prevent infection. In the case of the chickenpox vaccine, some people develop a rash after vaccination and the vaccine virus can shed from the rash. If this happens, individuals who arent immunocompetent or not yet vaccinated should stay away from the vaccinated individual until the rash is gone.

As such, though live virus vaccines can shed, the risk of infecting others is low because its the weakened version of the virus that is shed and individuals can take additional precautions to prevent infection. As such, Elizabeths claim that all live virus vaccines shed is misleading because it doesnt provide a complete picture of vaccine shedding. Particularly, it fails to mention that what is shed is the weakened version of the virus.

Herd immunity is achieved when the majority of a population is immune to a pathogen; this makes it hard for the pathogen to circulate in the population, which indirectly provides protection to the minority of individuals who arent immune. The safest way to achieve herd immunity is to vaccinate a very large percentage of the population. The World Health Organization has spoken against strategies that aim to achieve herd immunity through natural infection, since this would result in unnecessary cases and deaths. Therefore, claims that vaccines dont provide immunity and therefore cannot lead to herd immunity are inaccurate.

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NIH to study COVID-19 vaccine effectiveness on patients with compromised immune systems – FOX 5 NY

Sunday, May 2nd, 2021

Vaccine expert on differences between Johnson & Johnson and Pfizer, Moderna

Dr. Williams Moss, an epidemiologist and executive director of the International Vaccine Access Center at Johns Hopkins, shares the science behind adenovirus vs. mRNA vaccines.

BETHESDA, Md. - The National Institutes of Health announced on April 23, that it is launching a study to assess how people with compromised immune systems respond to COVID-19 vaccines.

The study has already begun enrolling participants at the National Institutes of Health Clinical Center in Bethesda, Maryland, the NIH said. It will be a single-site study with up to 500 people enrolled, 400 of whom will have primary or secondary immune system disorders and 100 without such conditions.

The study will be led by researchers at NIHs National Institute of Allergy and Infectious Diseases (NIAID).

Dr. Anthony Fauci, the nations leading expert on infectious diseases and the director of NIAID said, "Through large Phase 3 trials, several experimental COVID-19 vaccines were shown to be safe and effective and three are now authorized by the U.S. Food and Drug Administration for emergency use in the United States."

Dr. Ziyad Al-Aly from the St. Louis VA Healthcare System talks about a study that found an increased risk of death in patients who developed so-called 'long COVID.'

"People with immune disorders are typically excluded from trials of experimental vaccines, and this was the case in the COVID-19 vaccine trials. This new study will characterize the features and adequacy of immune responses to COVID-19 vaccination in people with a range of immune deficiencies and dysregulation syndromes and will provide valuable information about benefits and potential risks in these individuals," Fauci continued.

Previous research has raised questions about how well COVID-19 vaccines protect people with compromised immune systems.

RELATED: Vice President Harris tells UN it's time now to prepare for next pandemic

A study published on March 15 by researchers at Johns Hopkins University looked at how COVID-19 vaccines specifically protected organ transplant recipients. Transplant recipients take powerful immune-suppressing drugs to prevent organ rejection, which also increases their risk from the coronavirus.

Vaccines rev up the immune system to recognize the virus, something thats harder to do if someones immune cells arent in good working order.

For the Johns Hopkins study, researchers tested 436 people who had received new organs in recent years and were getting the Pfizer or Moderna vaccines. A few weeks after the first dose, 17% of the transplant recipients had developed antibodies against the coronavirus, said Dr. Dorry Segev, a Hopkins transplant surgeon who co-authored the study.

Of most concern were people whose transplant medications included a type called an anti-metabolite. They were far less likely to respond to the shot than those who dont require that kind of drug, the study in the Journal of the American Medical Association said.

RELATED:Activities you can safely do once fully vaccinated against COVID-19

The findings came after the U.S. Centers for Disease Control and Prevention said fully vaccinated people can relax some, but not all, of the masking and distancing precautions against the coronavirus.

Dr. David Mulligan, Yale Universitys chief of transplant surgery and immunology, said the study was a disappointment but not a surprise because people with weak immune systems dont respond as well to other vaccines.

Some transplant groups, including the American Society of Transplantation, already have issued cautions about that.

As for the most recent NIH study, scientists say they hope to better understand how people with immune deficiencies respond to COVID-19 vaccines.

"Currently, there are few published studies on the incidence and clinical presentation of COVID-19 disease in people who have immune deficiencies, especially those who have inborn conditions involving deficits or dysregulations in antibody or cell-based immune responses to infections," said study principal investigator Emily Ricotta, Ph.D., MSc, of the NIAID Laboratory of Clinical Immunology and Microbiology. "Our study aims to fill this knowledge gap."

This story was reported from Los Angeles. The Associated Press contributed.

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FACTCHECK COLUMN: Vaccines benefit those who have had COVID-19 – Montrose Daily Press

Sunday, May 2nd, 2021

The authorized COVID-19 vaccines have been found to be safe and effective in clinical trials and in real-world conditions. Out of more than220 million doses administered so farand clinical trials with thousands of participants, there is no evidence showing that vaccinating those with previous SARS-CoV-2 infections could beunsafe.

On the contrary,increasinglygrowingevidenceshowsonedoseofthevaccine benefits individuals whove recovered from the infection, boosting their immune response and providing them with full protection for a period of time.

Our study and several other studies show that there is a benefit, immunologically in people who were previously infected,E. John Wherry, director of the University of Pennsylvanias Institute for Immunology, told FactCheck.org in a phone interview.

Yet a number of viral postsquestionthe need of vaccinating those whove already recovered from COVID-19, andone of them, published by Robert F. Kennedy Jr.s anti-vaccination organization, falsely claims it could potentially cause harm, or even death.

Researchers told FactCheck.org that is not what the evidence is showing.

Theres no indication that vaccinating people who had previously had COVID is resulting in an increased risk of adverse events, Wherry said.

Wherry, who is one of the lead authors of astudylooking at the immune responses to the mRNA vaccines in individuals with and without previous infections, said people who recover from the disease show different levels of antibodies created by the immune system to identify and neutralize the virus. The vaccines, he said, improved the immunity response in individuals by raising the levels of neutralizing antibodies in those whove been infected.

Some people actually have fairly low antibody responses that are not sufficient to neutralize the virus, especially variant viruses. When you vaccinate them uniformly, you get high antibody titers [measurements] and high neutralization titers, so theres an improvement in at least one of the key metrics of immunity following vaccination, he said.

According to guidance by the Centers for Disease Control and Prevention, people whove already had COVID-19should be vaccinated anywaybecause experts do not yet know how long they are protected from getting sick again. Those whove gotten the disease get some protection by building whats called natural immunity. And although available evidence shows that reinfection is uncommon in the months following the first infection, theCDC saysthat may vary over time.

Available data suggest that previously infected individuals can be at risk of COVID-19 (i.e., reinfection) and could benefit from vaccination. Furthermore, data suggest that the safety profile of COVID-19 vaccines in previously infected individuals is just as favorable as in previously uninfected individuals, a spokesperson for the U.S. Food and Drug Administration told us in an email.

Up until now, the passive and activesurveillance systemsset up to monitor the safety of the COVID-19 vaccines have only foundrare adverse eventsassociated with the vaccines.

A small number of people (2 to 5 people per million vaccinated) have reported a severe allergic reaction called anaphylaxis. And the CDC and the FDA are studyinga small number of casesof people who experienced arare and severetype of blood clot with low platelets after getting the Johnson & Johnson vaccine. As a result, theagencies recommended a pausein the use of this product. On April 23, a CDC panel of advisersrecommended the pause be lifted.

No evidence of risk for previously infected individuals

Ina blog poston The Defender, a website owned by R.F.K. Jr.s organization, Childrens Health Defense, a freelance reporter writes that theres no science supporting the need of vaccinating people who have recovered from COVID-19. Theres a potential risk of harm, including death, in vaccinating those whove already had the disease or were recently infected, the post claimed.

Researchers dont agree, including one quoted by The Defender.

Dr. Colleen Kelley, an associate professor of medicine and epidemiology at Emory University School of Medicine andthe principal investigator for Modernas and Novavaxs phase 3 vaccine trials at Emory, is quoted by The Defender as saying people with previous infection get harsher side effects after vaccination. Her remarks came from aHuffPostarticle in March.

In a phone interview, Kelley told us that tolerable side effects are expected, and not always present. In the Moderna trials, there did not appear to be an increased rate of side effects among people who were antibody positive when they were vaccinated, she said.

There is absolutely no evidence that there is any harm for people to be vaccinated, who have previously had COVID disease,Kelley said.

The Defenders claims are mostly based on statements by Dr. Hooman Noorchashm, a formerassistant professor of surgeryat the University of Pennsylvania School of Medicine, who has beenwarning health officials, vaccine manufacturers and more recently university leadersof the potential danger of vaccinating people who have recently been infected with the novel coronavirus.

Noorchashm has been voicing his arguments widely, including on Fox News Tucker Carlson TodayandThe Defender podcast.But headmitsthey are based on a prognostication in that I have put it forth in the absence of clear evidence of it being a material risk.

Based on previous studies not related to the COVID-19 pandemic, Noorchashm argues that antigens of SARS-CoV-2 remain in the tissues of someone whos been infected for some time after theyve recovered. The vaccine, he says, reactivates the immune response, targeting the tissues where these antigens remain, causing further inflammation and damage, including to the vascularendothelium,the thin tissue that lines the heart and blood vessels.

Most pertinently, when viral antigens are present in the vascular endothelium or other layers of the blood vessel, and especially in elderly and frail with cardiovascular disease, the antigen specific immune response incited by the vaccine is almost certain to do damage to the vascular endothelium, he said in a Jan. 26lettersent to FDA officials and Pfizer executives. Such vaccine directed endothelial damage is certain to cause blood clot formation with the potential for major thromboembolic complications, at least in a subset of such patients.

In a phone interview with FactCheck.org, Noorchashm explained that all medical treatments, including vaccines, have some complications. And if those complications happen when a treatment is avoidable in this case, he says, vaccinating those whove recently been infected then thats potentially harmful.

His recommendation is to test peoples antibodies before vaccination and to delay vaccination for approximately eight months after infection. He and his wife, aphysician who died in 2017,fought for yearsto ban a tool used to remove uterine fibroids, after the procedure spread cancer into his wifes abdomen.

Dr. Steven Varga, a professor of microbiology and immunology at the University of Iowa whose lab studies immunopathology in respiratory virus infections, told us hes not aware of any scientific data that demonstrates that viral antigens persist long after the SARS-CoV-2 infection has gone away. And if there were, he says, there would likely be insufficient levels to drive such a robust immune response to cause the damage Noorchashm suggests.

Generally, once the virus is cleared, there can be some viral antigen that persists in various locations, so it is possible there could be some in the endothelium, Varga said. Again, Im not aware of any studies that have shown that to be the case. But even if there were small amounts of viral antigen, generally that shouldnt be enough viral antigen to induce the type of damage that would need to occur to have the kind of more severe outcome.

Dr. Donna Farber, a professor of microbiology and immunology at Columbia University focused on immunological memory, told us Noorchashms prognostication is not consistent with the data.

The data are that the virus is cleared from the lungs, the virus is cleared from the upper respiratory tract. And so if theres no virus, theres no antigen, Farber, who recently published astudy on the immune response to COVID-19 in the lungs, said in a phone interview.

Farber added that the protective immunity provided by the vaccine, neutralizing antibodies, do not cause the sort of harm Noorchashm is talking about. That could happen, she says as an example, if there was a virus hidden in cells and then a patient is given cytotoxic T cells,a type of immune cell that can kill infected cells or cancer cells.

But the chance of that happening in a vaccine and for a vaccine thats really targeting neutralizing antibodies and not, you know, the sort of a killer T cell response its just inconsistent with the science, she said.

Farber also said for most pathogens, our immune system requires repeated exposure to get protection over time. Thats why people get a vaccine for influenza every year, she said, regardless if theyve been exposed to the virus or not.

Seeing an antigen again and again, isnt bad for you. Its what we do all the time. And its what our immune system has evolved to do. And thats how it generates its best memory, she said.

This column was edited for space. See the whole column at FactCheck.org

Clarification, April 27: Although nothing in the article indicates that Dr. Noorchashm is a member of an anti-vaccination group, Dr. Noorchashm requested FactCheck to add that he is not anti-vaccine. He said he has been vaccinated against COVID-19.

SciChecks COVID-19/Vaccination Projectis made possible by a grant from the Robert Wood Johnson Foundation. The foundation hasno controlover our editorial decisions, and the views expressed in our articles do not necessarily reflect the views of the foundation. The goal of the project is to increase exposure to accurate information about COVID-19 and vaccines, while decreasing the impact of misinformation.

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IBD treatment blunts immune response to Covid-19 vaccines – iNews

Sunday, May 2nd, 2021

A common treatment for inflammatory bowel disease (IBD) blunts the immune response to a Covid-19 vaccine, a study has found.

Exeter University researchers measured antibody responses after vaccination with the Pfizer/BioNTech or the Oxford/AstraZeneca vaccine in 865 people treated with infliximab, an anti-tumour necrosis factor (anti-TNF) biologic drug, prescribed to around two million people worldwide.

Anti-TNF drugs are effective treatments for immune-mediated inflammatory diseases, but by suppressing the immune system, they can reduce vaccine effectiveness and increase risk of serious infection.

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IBD is a term mainly used to describe two conditions, ulcerative colitis and Crohns disease, both long-term conditions that involve inflammation of the gut. It affects at least one in 250 people of the UK population and the prevalence is rising.

The Exeter team found that people treated with infliximab had significantly lower concentrations of antibodies, when compared to 428 people on an alternative treatment, vedolizumab.

After a single dose of vaccine, only about one third of participants (103 of 328) treated exclusively with infliximab generated adequate levels of antibodies to the virus for the vaccine to be considered effective.

In participants simultaneously taking infliximab and immunomodulator drugs, such as azathioprine or methotrexate, the levels of antibodies were even lower after a single vaccine dose; only 125 of 537 met the threshold of a positive antibody test.

However, in a sub-group of people who had previously been infected with Covid-19, and also in the few patients studied who had already had a second dose of vaccine, the vaccine-triggered antibody responses rose significantly, indicating an effective response after two exposures.

Based on these observations, the researchers conclude that people taking anti-TNF drugs should be considered a priority for a second vaccination.

Co-author Dr Nick Powell, of Imperial College London, said: Although we know that this has been an incredibly difficult time for people with IBD, our research indicates that people treated with infliximab should consider that they are not protected from Covid-19 until they have had both doses of a vaccine and should continue to practice enhanced physical distancing and shielding if appropriate.

The study is published in the journal Gut.

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The future of animal nutrition includes clean feed – The Pig Site

Sunday, May 2nd, 2021

When talking about clean feed, one of the most important topics is gut health. A healthy gut can lead to healthier animals, and ultimately, an improved return on investment (ROI).

Clean feed is a major factor influencing the development of a healthy gut in young animals. Low-quality feed ingredients promote inflammation through pro-inflammatory cytokines and the proliferation of pathogenic bacteria leading to nutritional disorders, negatively impacting growth.

Many feed ingredients contain anti-nutritional factors (ANF) like non-starch polysaccharides, beta-conglycinin, high aromatic amino acids, oxidized lipids, and gluten prolamins, all of which promote gut inflammation. In response to gut inflammation, expression of pro-inflammatory cytokines increases followed by an oxidative stress response which leads to increased apoptosis and further upregulation of pro-inflammatory cytokines. If the response to inflammatory compounds in feed ingredients continues, the vicious circle will continue as well, leading to chronic inflammation, lowering ROI.

The gut microbiome is heavily influenced by the composition of feed consumed by young animals. Feed ingredients can promote the proliferation of symbiotic bacteria or pathogenic bacteria. Feed ingredients containing ANFs will shift the gut microbiome from symbiotic to pathogenic bacteria, promoting infectious inflammations. By shifting the microbiome towards pathogenic bacteria and continuing to feed ingredients with ANFs, it allows for bacterial fermentation which can increase the risk of diarrhea and nutrition-related diseases.

An example of an ANF are trypsin inhibitors (TI) in soybean meal (SBM). High TI are one of the greatest factors decreasing the quality of SBM fed to monogastric animals, subsequently impacting feed digestibility and increasing gut inflammation. When pigs were fed a diet of 38% SBM with 8.78 mg/g of TI, amino acid digestibility decreased by 13-26% while digestibility of crude protein was reduced by 23.3% (Chen et al., 2020). A similar trend has been shown in broiler chickens in which high TI reduces protein digestibility, decreasing body weight gain and increasing feed conversion ratio (FCR) (Rada et al., 2017).

This is true in the case of ruminants, as well. One of the leading causes of calf death is enteric infection. Improving calf gut health mitigates the risk of developing enteric infections while improving the immune system and overall health of the animals. There is also evidence to suggest that alteration of the microbiome at a young age leads to improved milk production (Steele et al., 2016; Dill-McFarland et al., 2017).

Evidently, keeping it simple with the use of clean ingredients promotes the development of a healthy gut leading to many additional benefits like reduced intervention and a greater return on investment. This is important for setting young animals up for success from the start, supporting their long-term health and performance.

Ensuring gut health through clean feed ingredients can lead to improvements in overall health, reducing the need for intervention through management practices. Establishing a healthy gut through clean feed decreases the incidence of diarrhea, reduces oxidative stress, and can diminish the need for antibiotics. Responses to these forms of stress also require a great deal of energy to activate the immune response. This results in energy from the feed being put towards the immune response, rather than towards growth. Feeding clean feed ingredients support health while fostering perfect growing conditions.

Enhancing immunity and overall health of young animals can translate to an improved return on investment (ROI). Feeding ingredients with lower ANF early on in life reduces gut inflammation and oxidative stress while supporting development of a healthy immune system and leading to lower FCRs and therefore higher ROI. A reduced need for management interventions can also reduce the cost of production as less labor is needed and less will be spent on antibiotics/AGPs or other medications. While AGPs are forbidden in Europe, they are still used around the world, but with clean diets AGPs become redundant and unnecessary, further improving ROI. Clean feed creates value both in terms of animal health and financials.

Hamlet Protein produces clean soy-based feed ingredients for young animals with significantly lower ANFs compared to conventional SBM. The patented production process is gentle and uses an enzymatic treatment to reduce the levels of the most harmful ANFs without damaging the protein or the amino acids. The process is monitored very closely, making sure customers receive the exact same high quality every time.

Feeding Hamlet Protein products in the starter diet of young animals has been shown to enhance nutrient absorption, increase body weight gain, decrease FCR, all while reducing the incidence of metabolic disease and need for treatment. The Hamlet Protein difference is providing young animal feed ingredients that aid in establishing a healthy gut to enhance performance and, ultimately, increase ROI.

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Use of PD-1/PD-L1 and VEGF Inhibition Combination Is Expanding – Pharmacy Times

Sunday, May 2nd, 2021

Antivascular endothelial growth factor (VEGF) therapy is used to treat a wide variety of malignancies, in the front-line setting and beyond.4 Sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals Inc) was the first VEGF tyrosine kinase inhibitor (TKI), approved in 2005 for the treatment of advanced renal cell carcinoma.5 After this approval, anti-VEGF therapies began expanding into other areas in cancer care in a similar manner to PD-1/PD-L1 inhibitors.

Results from clinical trials studying the combination of PD-1/PD-L1 and VEGF inhibitors for the treatment of various malignancies began to be published and FDA approvals followed shortly thereafter. The first approved combination of antiPD-1/PD-L1 and anti-VEGF therapy, atezolizumab (Tecentriq; Genentech, Inc) and bevacizumab (Avastin; Genentech, Inc), in December 2018, was for the treatment of metastatic nonsquamous nonsmall cell lung cancer.6 The same combination was also approved for the treatment of hepatocellular carcinoma in May 2020.7

Pharmacology

AntiPD-1/PD-L1 monoclonal antibodies, also termed checkpoint inhibitors, are referred to generally as immunotherapy, and more recently as immuno-oncology. These agents exert anticancer activity by binding PD-1 or PD-L1 that is present on the surface of tumor cells and CD8-positive T cells, thus blocking the interaction. When PD-1 and PD-L1 bind normally, it causes downregulation of the immune system. Therefore, the prevention of these inhibitory signals, in effect, stimulates the immune system to target tumors. Whether the agent is an antiPD-1 or antiPD-L1 monoclonal antibody, the effect is the same.8 At present, FDA-approved antiPD-1 monoclonal antibodies include pembrolizumab, nivolumab, and cemiplimab (Libtayo; Regeneron Pharmaceuticals, Inc), and antiPD-L1 monoclonal antibodies include atezolizumab, avelumab (Bavencio; EMD Serono), and durvalumab (Imfinzi; AstraZeneca Pharmaceuticals LP).9

Anti-VEGF therapies are subdivided into 3 subclasses: orally administered TKIs, intravenous (IV) monoclonal antibodies, and an IV recombinant fusion protein. The TKIs sorafenib, sunitinib (Sutent; Pfizer), pazopanib (Votrient; Novartis Pharmaceuticals Corporation), lenvatinib (Lenvima; Eisai Inc), regorafenib (Stivarga; Bayer HealthCare Pharmaceuticals Inc), cabozantinib (Cabometyx; Exelixis, Inc), axitinib (Inlyta; Pfizer), and vandetanib (Caprelsa; AstraZeneca Pharmaceuticals LP) are multikinase inhibitors, as they bind and antagonize several types of receptor tyrosine kinases in addition to VEGF.10 PDGFRs, FGFRs, and KIT inhibitors also lend their use in diverse malignancies according to driver mutations in these receptors.10

The anti-VEGF monoclonal antibodies are inherently more specific than the TKIs; those on the market include bevacizumab and ramucirumab (Cyramza; Eli Lilly and Company).9 Bevacizumab binds to circulating VEGF type A, preventing it from binding a VEGF receptor. Ramucirumab, on the other hand, binds to the extracellular portion of the VEGF receptor, thereby blocking the binding of VEGF and causing a similar effect.10

Lastly, ziv-aflibercept (Zaltrap; Sanofi-Aventis US LLC) is a recombinant fusion protein with limited indications; it acts as a decoy receptor for VEGF type A and B.11

Combination Therapy

Previous research results have elucidated the role of tumor-produced VEGF in solid tumor angiogenesis in addition to immune system downregulation, which allows for tumor growth and immune system escape.4,12 Although the antiangiogenetic effects of VEGF inhibitors are partly responsible for the disease responses observed, the inhibition of immune system downregulation caused by tumor-produced VEGF is another pharmacodynamic mechanism that can be exploited to achieve better outcomes.4

Considering the anti-immunosuppressive effects of VEGF inhibitors, it stands to reason that synergy is seen when VEGF inhibitors are combined with PD-1/PD-L1 inhibitors.13 Therefore, investigators and drug manufacturers are exploring this combination in several malignancies in which PD-1/PD-L1 inhibitors and VEGF inhibitors currently play a role in treatment, exclusive of one another.

The fundamental approach taken in combination chemotherapy is such that the individual agents in a regimen have differing dose-limiting toxicities and mechanisms. In this manner, multiple agents can be combined with differing adverse effects so that toxicities are not additive. Rather, toxicities that are separated over a range of types can be individually managed while the additive or even synergistic efficacy of all the agents is maintained.14

The strategy of combination therapy began with cytotoxic chemotherapy regimens and has since evolved into targeted and monoclonal antibody therapies, with PD-1/PD-L1 and VEGF inhibitors representing a relatively novel pairing in cancer care. The Table shows a summary of PD-1/PD-L1 and VEGF inhibitor combinations currently approved by the FDA.

Patient Eligibility

AntiPD-1/PD-L1 monoclonal antibodies are often approved with minimum requirements of PD-L1 expression upon tumor staining, which is measured in combined positivity score (CPS) or tumor proportion score (TPS). Tumors with microsatellite instabilityhigh (MSI-H) status or mismatch repair deficiency (dMMR) may be another condition often attached to the indication for antiPD-1/PD-L1 monoclonal antibodies. Notably, only 1 indication for a PD-1/PD-L1 and VEGF inhibitor combination has 1 of these conditions: patients with advanced endometrial cancer must not have MSI-H or dMMR disease status to qualify for treatment with pembrolizumab and lenvatinib.15 No other PD-1/PD-L1 and VEGF inhibitor combinations have these requirements included with their FDA approval, affording more opportunities for patients to benefit from therapy.

Dozens of clinical trials evaluating PD-1/PD-L1 and VEGF inhibitor combinations are listed on ClinicalTrials.gov, and most are actively recruiting. They are assessing combinations along with the addition of chemotherapy and other targeted therapies. Given the number of trials in process and the results previously seen, it is likely that more approvals of this combination are on the horizon.

Conclusions

PD-1/PD-L1 inhibitors continue to change the cancer treatment landscape, and the relatively new combination with VEGF inhibitors represents a promising option for patients with various malignancies. Most likely, the trend of combined PD-1/PD-L1 and VEGF inhibition therapy will keep expanding into areas in which PD-1/PD-L1 and VEGF inhibitors are already being used.

VINCENT J CASCONE, PHARMD, BCOP, is a clinical oncology pharmacist at the University of Kansas Health System in Kansas City.

REFERENCES

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Rise and Fall of Antibiotic Resistance During Infection Driven by Host Immunity and Rapid Evolution – Technology Networks

Sunday, May 2nd, 2021

Antibiotic resistance poses a serious threat to human health. Resistant infections now cause more than 750,000 deaths per year and are predicted to increase to 10 million deaths per year by 2050. It is known that treating patients with antibiotics is associated with the emergence of resistance - and worse outcomes for patients. But how resistance emerges during infections remains poorly understood.

In a new study published today in Nature Communications, an international team led by Oxford University scientists reports that rapid bacterial evolution interacts with host immunity to shape both the rise, and fall, of resistance during infection.

This study highlights the need to understand better how our immune system works with antibiotics to suppress bacterial infections.

Craig MacLean, co-author and Professor of Evolution and Microbiology at the University of Oxford, said: Our study suggests that natural immunity can prevent resistance during infection and stop the transmission of resistant strains between patients. Exploiting this link could help us to develop new therapeutics to use against bacterial pathogens and to better use the antibiotics that we have now.

The collaborators discovered that antibiotic treatment killed the overwhelming majority of bacteria causing the infection, but bacteria with resistant mutations continued to grow and replicate during treatment. However, they also learned that the resistant mutants had low competitive ability, leading to the loss of resistance after treatment as resistant mutants were replaced by sensitive competitors that managed to escape antibiotic treatment.

Professor MacLean said: Both the rise and fall of resistance during infection are simple and elegant examples of evolution by natural selection.

Host immunity helped to suppress the infection, probably removing >90% of resistant mutants that were present at the start of antibiotic treatment. Host immunity also eventually eliminated the resistant populations that were present after treatment.

The team was able to generate these insights by tracking changes in the bacterial population in a single subject at an unprecedented level of resolution, and combining this with data on patient health and immune function. The bacterial pathogen in this case was Pseudomonas aeruginosa, an opportunistic pathogen that mainly causes infections in hospitalised patients and in people with cystic fibrosis or bronchiectasis.

Professor MacLean said: This is the kind of study that I could have only dreamed of 10 years ago. Technological progress was certainly important to this project, but the real key to our success was increased collaboration and cross-talk between medical researchers and evolutionary biologists.

The research described in this paper is part of a larger ASPIRE-ICU study, which stands for Advanced understanding of Staphylococcus aureus and Pseudomonas aeruginosa Infections in EuRopE Intensive Care Units. The ASPIRE-ICU trial was conducted by the COMBACTE consortium and brought together multiple collaborators from leading academic research labs along with AstraZeneca scientists. The COMBACTE consortium is a major academia-industry collaboration exploring new approaches to antimicrobial resistance.

ReferenceWheatley R, Diaz Caballero J, Kapel N, et al. Rapid evolution and host immunity drive the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection. Nature Comms. 2021;12(1):2460. doi:10.1038/s41467-021-22814-9

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Pooled CRISPR screening identifies m6A as a positive regulator of macrophage activation – Science Advances

Sunday, May 2nd, 2021

Abstract

m6A RNA modification is implicated in multiple cellular responses. However, its function in the innate immune cells is poorly understood. Here, we identified major m6A writers as the top candidate genes regulating macrophage activation by LPS in an RNA binding protein focused CRISPR screening. We have confirmed that Mettl3-deficient macrophages exhibited reduced TNF- production upon LPS stimulation in vitro. Consistently, Mettl3flox/flox;Lyzm-Cre mice displayed increased susceptibility to bacterial infection and showed faster tumor growth. Mechanistically, the transcripts of the Irakm gene encoding a negative regulator of TLR4 signaling were highly decorated by m6A modification. METTL3 deficiency led to the loss of m6A modification on Irakm mRNA and slowed down its degradation, resulting in a higher level of IRAKM, which ultimately suppressed TLR signalingmediated macrophage activation. Our findings demonstrate a previously unknown role for METTL3-mediated m6A modification in innate immune responses and implicate the m6A machinery as a potential cancer immunotherapy target.

Macrophages, serving as the first line of host defense, recognize pathogen-associated molecular patterns (PAMPs) of invading pathogens and damage-associated molecular patterns (DAMPs) from stressed or injured cells. These processes involve pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) (1). Depending on their genetic background and environmental stimuli, macrophages can be polarized to either an M1-like proinflammatory or tumoricidal phenotype with high capacity for antigen presentation and T cell activation or to an M2-like anti-inflammatory or protumoral phenotype with immunosuppressive function (24). Activated macrophages produce large numbers of chemokines and proinflammatory cytokines that attract and activate T cells to eliminate the invading pathogens. Tumor-associated macrophages (TAMs) within the tumor microenvironment represent a functional heterogeneous cell population that has a critical role in orchestrating tumor initiation and progression (3, 5, 6). Macrophage-centered strategies, including macrophage-targeting and TAM tumor-promoting blockade, began to enter clinical trials and show great potential for macrophage-based immunotherapy (3, 6, 7). Therefore, understanding the signaling involved in the activation and plasticity of TAMs will help develop better strategies for cancer immunotherapy.

The discovery of the components of the TLR signaling pathways has significantly advanced our knowledge of innate immune responses, which represent one of the most important evolutionarily conserved innate mechanisms for sensing invading pathogens. One of the most studied TLRs, TLR4, stimulates the myeloid differentiation primary response protein 88 (MyD88)- and TIR domain-containing adapter protein-inducing interferon (TRIF)dependent pathways, activating the transcription factor nuclear factor B (NF-B) and mitogen-activated protein kinases (MAPKs) and consequently inducing type I interferons and inflammatory cytokines such as tumor necrosis factor (TNF-) and interleukin-6 (IL-6) (8, 9). It has been demonstrated that negative regulation of the TLR signaling is strongly associated with the pathogenesis of inflammation and autoimmune diseases (1013). We and others have shown that IL-1 receptorassociated kinase 3 (IRAK3), also known as IRAKM, is an essential negative regulator of TLR signaling pathways (1417). The expression of IRAKM induced by the activation of macrophages prevents the dissociation of IRAK and IRAK4 from MyD88 and inhibits the formation of IRAK-TRAF6 (TNF receptorassociated factor 6) complexes. These effects of IRAKM suppress NF-B activation and the expression of inflammatory cytokines and chemokines in macrophages, preventing the development of pathologic immune reactions (10, 14). However, it remains unknown whether the posttranscriptional regulation, particularly the epigenetic modification of RNA, is involved in the control of innate immune responses in macrophages.

RNA modifications, especially the formation of N6-methyladenosine (m6A), represent one of the most delicate posttranscriptional mechanisms regulating gene expression (18). m6A, the most abundant mRNA modification, is modulated by m6A writer, eraser, and reader. The m6A writer complex comprises the catalytic core consisting of methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14) and the adapter proteins Wilms tumor 1 associated protein (WTAP), RNA binding motif protein 15 (RBM15), vir like m6A methyltransferase associated (VIRMA), zinc finger CCCH-type containing 13 (ZC3H13), and Cbl proto-oncogene like 1 (CBLL1) (19, 20). It has been extensively documented that m6A is involved in pre-mRNA splicing, mRNA export, initiation, translation, and, predominantly, mRNA degradation (21, 22). m6A methylation has been regarded as a key regulator in various biological and pathological processes (19, 21), but its function in the immune system has not been recognized until recently (23). Our previous studies demonstrated that silencing the m6A methyltransferase METTL3 disrupts T cell homeostasis by targeting the IL-7/signal transducer and activator of transcription 5 (STAT5)/suppressor of cytokine signaling (SOCS) pathway and causes a systemic loss of the suppressive function of regulatory T cells (Tregs) (24, 25). The METTL3-mediated m6A modification on Cd40, Cd80, and TIR domain containing adaptor protein (Tirap) transcripts enhances their translation in dendritic cells, promoting dendritic cell activation (26). Together, these studies indicate that m6A methylation plays an essential role in the maintenance of immune cell homeostasis and function. In addition, the deletion of m6A demethylase alkB homolog 5, RNA demethylase (ALKBH5) in macrophages has been recently demonstrated to inhibit viral replication in vivo and in vitro (27, 28). The m6A reader YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) suppresses interferon-dependent antiviral responses by promoting forkhead box O3 (FOXO3) translation (29). In addition, the loss of YTHDF1 in classical dendritic cells enhances the cross-presentation of tumor antigen and the cross-priming of CD8+ T cells in vivo (30). These findings, which highlight the significance of m6A modification in the immune response, prompted us to explore further the function of METTL3-mediated m6A modification in macrophage activation and polarization and the role of TAMs during tumorigenesis.

Here, we have identified METTL3 as a positive regulator of the innate response of macrophages by pooled RNA binding protein (RBP) CRISPR-Cas9 screening. We have demonstrated that Mettl3 deficiency in macrophages attenuates their ability to fight against pathogens and eliminate tumors in vivo, suggesting that METTL3-mediated m6A modification is required for proper activation of macrophages. We have shown that Mettl3 deficiency impairs the TLR4 signaling pathway in macrophages by inhibiting the degradation of Irakm transcripts. Thus, the present work uncovers the epitranscriptional control of the innate immune response of macrophages, providing a novel strategy to target the m6A machinery for macrophage-based cancer immunotherapy.

The posttranscriptional regulation of TLR signaling and proinflammatory cytokines is fine-controlled during macrophage activation. However, these processes have not been adequately studied. Therefore, we have investigated the posttranscriptional events in mRNA metabolism that are tightly regulated by RBPs to orchestrate fundamental cellular processes. To screen RBPs critical for macrophage activation, we prepared customized pooled RBP CRISPR-Cas9 screens. TNF- was selected as the readout for the targeted RBP CRISPR screening since this cytokine represents the primary response during macrophage activation and can be easily detected by flow cytometry. Moreover, TNF- has also been shown to act as a master regulator of inflammatory cytokine synthesis, and its aberrant production is associated with the pathogenesis of several inflammatory diseases (31, 32). We have compiled and synthesized a targeted lentivirus mini-library with 7272 single guide RNAs (sgRNAs) targeting 782 genes coding for classical RBPs known in the mouse genome, as well as positive and negative controls with 10 gRNAs for each gene (listed in the Supplementary Materials). We have also generated a Raw 264.7 macrophage cell line stably expressing Cas9 and validated its functionality and effectiveness (fig. S1A). In each of the two replicate screens, 109 Cas9-expressing Raw 264.7 cells were infected with a lentivirus library at a multiplicity of infection (MOI) of 0.3. After selection with puromycin for 7 days, cells were stimulated with LPS and sorted on the basis of TNF- expression (Fig. 1A and fig. S1B). sgRNAs from cells with high (TNF-Hi) and low (TNF-Low) TNF- expression and from cells harvested on the last day of selection before sorting (presort) were amplified and sequenced. The top-ranked sgRNA enriched in TNF-Hi or TNF-Low cells showed high concordance between biological screen replicates (Fig. 1B). As expected, sgRNAs targeting known positive regulators (e.g., Myd88 and Irf3) and negative regulators (e.g., Zfp36 and Tnfaip3) of the LPS response were enriched in TNF-Low and TNF-Hi cells, respectively, demonstrating the success and high quality of the screens (Fig. 1C).

(A) Scheme of pooled CRISPR-Cas9 screening of RBPs playing critical roles in macrophage activation. Briefly, Cas9-expressing Raw 264.7 cells were infected with lentivirus library containing sgRNAs targeting RBP genes in the mouse genome. After selection with puromycin for 7 days, the cells were stimulated with LPS and sorted by flow cytometry on the basis of the expression levels of TNF-. (B) Venn diagrams showing the overlap between the top 100 ranked candidate genes enriched in TNF-Low and TNF-Hi populations in two replicate screens. (C) Volcano plot showing sgRNA-targeted genes enriched in the TNF-Hi (blue) and TNF-Low (red) populations. Known positive regulators (purple), negative regulators (green), and m6A modulators (black) of TNF- production in macrophages are highlighted. (D) Protein level of METTL3 and the overall RNA m6A methylation levels in WT and Mettl3-KO Raw 264.7 cells were measured by Western blotting and m6A dot blot assay. (E) Expression of TNF- in METTL3-depleted and control Raw 264.7 cells after LPS stimulation measured by flow cytometry. MFI, median fluorescence intensity; NT, not treated. (F) GO enrichment analysis of down-regulated transcripts in Mettl3-KO Raw 264.7 cells compared to WT control cells. (G) Heatmap illustrating the expression of transcripts downstream of the TLR4 signaling pathway in Mettl3-deficient and WT Raw 264.7 cells. (H) Expression of TNF- in bone marrowderived macrophages (BMDMs) from Mettl3flox/flox;Lyzm-Cre and Mettl3flox/flox control mice upon LPS stimulation measured by flow cytometry. Data are shown from two experiments (B and C), as a representative result of three independent experiments (D), or as means SEM (E and H).*P < 0.05 and ****P < 0.0001 (unpaired two-tailed Students t test).

Besides the known regulators, we have also found that sgRNAs targeting the components of the m6A writer complexMettl3, Mettl14, Rbm15, and Nudt21were highly enriched in the top-ranked hits in TNF-Low cells. These results indicate important functions and a general role of m6A modification in the activation of macrophages (Fig. 1C). To validate the involvement of m6A in macrophage activation, Mettl3 was knocked out in Raw 264.7 cells using CRISPR with new sgRNAs, and the deficiency of Mettl3 and the substantial decrease in the overall RNA m6A methylation level were confirmed (Fig. 1D). Consistent with the CRISPR screen results, the expression of TNF- and IL-6 in Mettl3-depleted Raw 264.7 cells stimulated with LPS was markedly reduced in comparison to control cells (Fig. 1E and fig. S1, C to H). To further explore the biological effects of m6A deficiency on macrophages, we performed RNA sequencing (RNA-seq) analysis on Mettl3 knockout (KO) and wild-type (WT) control Raw 264.7 cells. The Gene Ontology (GO) enrichment analysis documented that the down-regulated transcripts in Mettl3-KO Raw 264.7 cells were enriched in innate immune response related to defense and external stimulus (Fig. 1F). Notably, in both replicates of RNA-seq, transcripts of the downstream components of the TLR4 signaling pathway, such as proinflammatory cytokines (Tnf-, Il-6, Il-1, Il-18, and Il-23) and costimulation molecules (Cd86), were down-regulated in Mettl3-deficient cells (Fig. 1G), suggesting that METTL3 has a critical function in controlling the innate immune response of Raw 264.7 macrophages.

To further confirm the biological role of the m6A modification in macrophages, Mettl3 conditional KO (CKO) mice were generated by crossing Mettl3flox/flox mice with mice expressing Cre recombinase under the control of lysozyme 2 promoter (Lyzm-Cre). We have documented the loss of both the METTL3 protein and the overall m6A modification in bone marrowderived macrophages (BMDMs) from Mettl3flox/flox;Lyzm-Cre mice (fig. S1I). No differences in the frequency of major immune cell populations were observed between Mettl3flox/flox mice and Mettl3flox/flox;Lyzm-Cre mice in steady state, indicating that the depletion of Mettl3 did not affect the development and maturation of macrophages (fig. S1J). Next, we examined whether METTL3 affects macrophage activation. Consistent with the results obtained in Raw 264.7 cells, BMDMs from Mettl3flox/flox;Lyzm-Cre mice showed significantly decreased expression of proinflammatory cytokines, such as TNF-, IL-6, IL-1, and IL-12, upon LPS stimulation (Fig. 1H and fig. S1K). Together, these results demonstrate that METTL3 promotes the activation of macrophages.

Notably, the m6A readers, including YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2, IGF2BP1, IGF2BP2, IGF2BP3, HNRNPC, and HNRNPA2B1, did not reach significance in either TNF-Low or TNF-High population (fig. S2A and table S1), indicating that these genes either play a minimal role or have redundant functions in regulating the LPS-induced Tnf- production. To further assess the functional role of m6A readers in macrophages, small interfering RNAs (siRNAs) were used to knock down the expression of Ythdf2 and other readers, including Ythdf1, Ythdf3, and Ythdc1 in bone marrow derived macrophages (BMDMs) (fig. S2B). As shown in fig. S2C, we found that knocking down Ythdf2, Ythdf3, or Ythdc1 individually had a minor impact on Tnf- expression upon LPS stimulation, whereas knocking down Ythdf1 decreased the expression of Tnf-, and markedly higher down-regulation of Tnf- was seen when knocking down the expression of Ythdf1, Ythdf2, and Ythdf3 simultaneously. These results suggested the functional redundancy of YTHDF proteins in the innate immune response of macrophages (33, 34). In addition to the involvement of m6A modification in the activation of macrophages by LPS, other pathways associated with the mRNA metabolic process have also been found by GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the top 100 ranked hits in TNF-Hi and TNF-Low cells (fig. S2, D to G), which merits further exploration.

Upon recognizing invading pathogens, macrophages are activated to produce proinflammatory cytokines, such as TNF- and IL-6, that enhance the defense response of the host, facilitating pathogen clearance. To test the screen results in vivo, we investigated the physiological role of m6A modification in the macrophage-mediated defense against LPS-producing Gram-negative bacteria. For this purpose, Mettl3flox/flox; Lyzm-Cre mice and Mettl3flox/flox littermates were infected orally with S. typhimurium and sacrificed 4 days after infection to assess the inflammation and bacterial load in the intestine and other organs. Mettl3flox/flox;Lyzm-Cre mice showed significantly lower body weight than Mettl3flox/flox littermates (Fig. 2A) and had a higher bacterial load in the feces and cecum (Fig. 2, B to D). Furthermore, Mettl3flox/flox; Lyzm-Cre mice had a higher bacterial burden in the spleen and liver than Mettl3flox/flox littermates (Fig. 2, E and F). Together, these data suggest that METTL3 promotes the antibacterial activity of macrophages in vivo.

(A) Body weight of Mettl3flox/flox;Lyzm-Cre (n = 14) and their Mettl3flox/flox littermates (n = 10) measured 2 and 3 days after S. typhimurium infection. (B to F) Bacteria load of the feces (B and C), cecum (D), spleen (E), and liver (F) of infected Mettl3flox/flox;Lyzm-Cre (n = 14) and Mettl3flox/flox littermates (n = 10) measured by counting colony-forming units (CFU) in cultures of serially diluted homogenates of organs on MacConkey agar plates. Data are shown as representative results of three independent experiments (A to F) or as means SD of indicated determinants (B to F). *P < 0.05 and **P < 0.01 (unpaired two-tailed Students t test).

Given the function of m6A in promoting macrophage activation, we next sought to determine the role of METTL3 in macrophage-mediated antitumor immunity. Therefore, MC38 murine colon adenocarcinoma cells were subcutaneously implanted into the flanks of Mettl3flox/flox; Lyzm-Cre mice and their Mettl3flox/flox littermates. The growth of tumors was significantly faster in Mettl3flox/flox;Lyzm-Cre mice (Fig. 3, A and B, and fig. S3A). The mice were sacrificed 3 weeks after injection, and tumor-infiltrating immune cells were characterized by flow cytometry and real-time quantitative polymerase chain reaction (qPCR). There was no significant difference in the percentage of tumor-infiltrating lymphocytes between Mettl3flox/flox;Lyzm-Cre mice and Mettl3flox/flox littermates (fig. S3B). Notably, TAMs from Mettl3flox/flox;Lyzm-Cre mice exhibited reduced M1-like markers, such as the proinflammatory cytokine TNF- and the costimulatory protein CD86 (Fig. 3, C to E, and fig. S3C), while the expression of the mannose receptor CD206, a well-established M2-like marker, was increased in comparison with TAMs from Mettl3flox/flox mice (Fig. 3F and fig. S3C). These differences indicate that Mettl3 deficiency promotes the immunosuppressive function of TAMs. In addition, the expression of major histocompatibility complex II (MHC II) was comparable in TAMs from Mettl3flox/flox;Lyzm-Cre mice and Mettl3flox/flox littermates (fig. S3C). Consistent with these observations, both tumor-infiltrating CD4+ and CD8+ T cells from Mettl3flox/flox;Lyzm-Cre mice displayed a more exhausted phenotype, as evidenced by the elevated expression of the immune checkpoint receptor programmed cell death 1 (PD-1) (Fig. 3, G and H, and fig. S3D). Furthermore, in comparison with Mettl3flox/flox mice, BMDMs from Mettl3flox/flox;Lyzm-Cre mice were characterized by blunted TNF- production after the stimulation with MC38 tumor culture medium (TCM) (Fig. 3, I and J) and increased formation of the M2-like marker Arg-1 after either TCM or IL-4 stimulation (Fig. 3K and fig. S3E). Collectively, these data demonstrate that METTL3 promotes the tumoricidal ability of macrophages by facilitating the polarization bias of TAMs toward the M1 type macrophages.

MC38 cells were subcutaneously injected into the flanks of Mettl3flox/flox;Lyzm-Cre mice and their Mettl3flox/flox littermates. The tumor was excised, and tumor-infiltrating cells were characterized by flow cytometry and real-time qPCR. (A) Representative images of tumors excised from Mettl3flox/flox;Lyzm-Cre mice (n = 10) and Mettl3flox/flox littermates (n = 10) 21 days after cell injection. Photo credit: Jiyu Tong, Shanghai Jiao Tong University School of Medicine. (B) Tumor growth in Mettl3flox/flox;Lyzm-Cre mice (n = 10) and Mettl3flox/flox littermates (n = 10). (C and D) Relative expression of Mettl3 (C) and Tnf- (D) in TAMs from Mettl3flox/flox;Lyzm-Cre mice (n = 4) and Mettl3flox/flox littermates (n = 4) measured by real-time qPCR. (E and F) Flow cytometry profile and MFI of CD86-positive (E) and CD206-positive (F) TAMs from Mettl3flox/flox;Lyzm-Cre mice (n = 4) and Mettl3flox/flox littermates (n = 4). (G and H) Fractions of intratumoral PD-1positive CD4+ T cells (G) and PD-1positive CD8+ T cells (H) measured by flow cytometry (n = 3). (I and J) BMDMs from Mettl3flox/flox;Lyzm-Cre mice and Mettl3flox/flox littermates were stimulated with medium conditioned by MC38 tumor cells in vitro. The expression of TNF- was measured by flow cytometry and shown as a histogram (I) and MFI (J). Arg-1 expression in TAMs from Mettl3flox/flox;Lyzm-Cre mice and Mettl3flox/flox littermates measured by real-time qPCR after TCM or IL-4 treatment. Data are shown as representative results of three independent experiments (A, E, F, and I), as means SD (B, G, and H), or as means SEM (C to F, J, and K). *P < 0.05 and ***P < 0.001 (unpaired two-tailed Students t test).

To distinguish whether macrophage activation was impeded by the disruption of m6A modification rather than an m6A-independent activity of METTL3, we performed rescue experiments by overexpressing WT METTL3 (METTL3-WT) or catalytic mutant METTL3 (METTL3-MUT) in BMDMs from Mettl3flox/flox;Lyzm-Cre mice and Mettl3flox/flox littermate controls. The expression of TNF- in BMDMs from Mettl3flox/flox;Lyzm-Cre animals could only be restored by the Mettl3-WT, but not Mettl3-MUT constructs (fig. S4A). Since Tnf- mRNA can also be m6A-modified according to the m6AVar database, we hypothesized that Tnf- might be directly regulated by m6A. First, the degradation rate of Tnf- mRNAs was measured using RNA decay assays. Both Mettl3-depleted and WT Raw 264.7 cells were treated with the transcription inhibitor actinomycin D, and the changes in the abundance of Tnf- transcripts over time were measured by qPCR. The degradation of Tnf- mRNAs was similar in Mettl3-depleted Raw 264.7 cells and WT control cells (fig. S4B). Next, a mutagenesis assay was performed to directly assess the effect of m6A modification on TNF- expression. The assay used a WT Tnf- construct in which WT Tnf- 5 untranslated region (5UTR) and WT Tnf- 3UTR were replaced with either Tnf- 5UTR-MUT or Tnf- 3UTR-MUT harboring a point mutation in m6A sites predicted according to the m6AVar database (fig. S4C). The coding region of Tnf- was substituted with a green fluorescent protein (GFP) coding region to allow direct measurement of TNF- expression. A similar level of GFP expression was observed when human embryonic kidney (HEK) 293 cells were transfected with the same amount of each construct (fig. S4D). Therefore, these experiments demonstrated that although macrophage activation was indeed regulated by the m6A catalytic activity of METTL3, Tnf- mRNA was not the direct target of the m6A modification.

It is well established that the engagement of PAMPs or DAMPs with TLR4 receptors activates MyD88- and TRIF-dependent pathways and ultimately induces the synthesis of proinflammatory cytokines required for pathogen clearance or the destruction of tumor cells (6, 35). Since a defective expression of a broad range of cytokines was observed (Fig. 1G and fig. S1K), we hypothesized that the TLR4 receptor and its downstream pathway were compromised in Mettl3-deficient macrophages and could represent the direct m6A targets. Upon LPS stimulation, the phosphorylation of p65, p38, c-Jun N-terminal kinase (JNK), and extracellular signalregulated kinase (ERK) in Mettl3-deficient BMDMs was markedly decreased, but the total levels of these proteins were comparable between BMDMs from Mettl3flox/flox;Lyzm-Cre mice and their Mettl3flox/flox littermates (Fig. 4A). These data indicate that the Mettl3 deficiency probably affects molecules upstream of the NF-B and mitogen-activated protein kinase (MAPKs) pathways. Therefore, we examined the expression levels of essential upstream adaptors in the TLR4 pathway, including Tirap, Myd88, Traf6, Irak1, Irak4, Trif, and Tram, using real-time qPCR. The expression of these key adaptors was similar in WT and Mettl3-deficient BMDMs (Fig. 4B). However, we have noted that the mRNA and protein levels of Irakm, a well-established negative regulator of the TLR signaling pathway, were remarkably increased in Mettl3-deficient BMDMs in either steady-state or upon LPS stimulation (Fig. 4, A and C). The expression of IRAKM in WT macrophages was reduced immediately after LPS stimulation and began to recover 2 hours after TLR4 activation. This phenomenon was strongly inhibited in Mettl3-KO macrophages, resulting in a sustained overexpression of IRAKM (Fig. 4A and fig. S4E). Thus, we have raised the possibility that the overexpression of IRAKM caused by Mettl3 deficiency is responsible for the inhibition of TLR4 activation. To test this hypothesis, rescue experiments were performed by introducing either Irakm small hairpin RNA (shRNAs) (sh-Irakm) or control shRNAs (sh-CTL) into Mettl3-deficient BMDMs (Fig. 4D). Consistent with our prediction, the decrease in TNF- production in Mettl3-deficient BMDMs was largely reversed by the shRNA-mediated knockdown of Irakm (Fig. 4E). Together, these data indicate that the overexpression of Irakm in Mettl3-deficient macrophages suppresses the TLR4 signaling and consequently inhibits macrophage activation.

(A) Activation of the TLR4 signaling pathway in Mettl3-KO and Mettl3-WT BMDMs upon LPS stimulation was analyzed by Western blotting of p65, JNK, p38, ERK, and IRAKM. (B) Relative expression of Tirap, Myd88, Traf6, Irak, Irak4, Trif, and Tram in Mettl3flox/flox;Lyzm-Cre mice and Mettl3flox/flox littermates measured by real-time qPCR. (C) Relative expression of Irakm in control (NT) and LPS-treated Mettl3flox/flox;Lyzm-Cre and Mettl3flox/flox littermates measured by real-time qPCR. (D) Knockdown efficiency of shRNA targeting Irakm in BMDMs measured by real-time qPCR (n = 3). (E) TNF- synthesis in WT BMDMs transfected with control shRNA (sh-CTL) and Mettl3-deficient BMDMs transfected with sh-CTL or IRAKM shRNA (sh-IRAKM) measured by flow cytometry (n = 3). Data are shown as representative results of three independent experiments (A) or as means SEM (B to E). **P < 0.01 and ***P < 0.001 (unpaired two-tailed Students t test).

In addition, we tested other TLR pathways known to be regulated through IRAKM, especially TLR3 and TLR9. Similarly, TNF- production of BMDMs from Mettl3flox/flox; Lyzm-Cre mice was significantly decreased upon poly (I:C) or CpG stimulation (fig. S5A and S5B). Thus, m6A regulates TLR-mediated macrophage activation through Irakm.

RNA m6A methylation is involved in multiple aspects of RNA metabolism (36), predominantly affecting RNA stability. Mettl3 deficiency results in a significantly decreased m6A marker and, in turn, retards RNA decay of m6A target transcripts (37, 38). To assess whether the deletion of Mettl3 can decrease m6A methylation of Irakm mRNA, we profiled the transcriptome-wide m6A modification in WT and Mettl3-deficient Raw 264.7 cells using m6A immunoprecipitation followed by high-throughput sequencing (MeRIP-seq). Specific m6A peaks were clearly enriched in the 3UTR of Irakm mRNAs in WT cells, but the deletion of Mettl3 eliminated the Irakm m6A peaks completely (Fig. 5A). Notably, we did not detect significant m6A peak reduction in the Tnf- transcript (fig. S6A) and did not observe any significant m6A peaks throughout Il-6 transcript (fig. S6B), indicating that Tnf- and Il-6 are not direct m6A targets in macrophages. In agreement with the sequencing data, MeRIP-qPCR demonstrated that Irakm mRNA from WT but not Mettl3-deficient macrophages was immunoprecipitated by m6A-specific antibody (Fig. 5B). Together, these findings document that Irakm transcripts are bona fide m6A targets in macrophages.

(A) Specific m6A peaks enriched in the 3UTR of Irakm mRNAs in Raw 264.7 macrophages profiled using MeRIP-seq. CDS, coding sequences. (B) m6A peaks enriched in the 3UTR of Irakm mRNAs in WT cells were lost in Mettl3-KO Raw 264.7 cells. (C) WT or Mettl3-deficient BMDMs were treated with the transcription inhibitor actinomycin D, and the level of Irakm transcripts was measured over time. (D) Relative luciferase activity of pGL4-luc2 with WT-3UTR (IRAKM-WT) or with IRAKM-3UTR containing mutated m6A sites (IRAKM-MUT) transfected into HEK293T cells was measured. The firefly luciferase activity was normalized to Renilla luciferase activity. Data are shown as representative results of three independent experiments (A) or as means SEM (B to D). **P < 0.01 and ****P < 0.0001; NS, not significant (unpaired two-tailed Students t test).

To further test whether the up-regulation of IRAKM resulted from the decreased degradation of m6A-deficient Irakm transcripts, we have performed RNA decay assays by treating either WT or Mettl3-deficient BMDMs and Raw 264.7 cells with actinomycin D and measured the abundance of Irakm transcripts over time (Fig. 5C and fig. S6C). At 3 hours after actinomycin D treatment, Irakm mRNA level was significantly higher in Mettl3-deficient BMDMs and Raw 264.7 cells than in the WT control cells (Fig. 5C and fig. S6C). To directly evaluate the role of m6A in modulating the stability of Irakm mRNA, luciferase reporter assays were conducted. In comparison with WT Irakm-3UTR (Irakm-WT) constructs, the ectopically expressed constructs harboring m6A mutant Irakm-3UTR (Irakm-MUT) showed substantially increased luciferase activity (Fig. 5D). We also constructed a plasmid harboring IRAKM with either WT-3UTR or m6Amut-3UTR. Consistent with our previous results, we found that the transcription level of Irakm with m6Amut-3UTR was notably higher than that of Irakm with WT 3UTR (fig. S6D). In addition, we also tested the effect of METTL3 deficiency on transcription of Irakm mRNA. As shown in the fig. S6E, we found that the transcription rate of Irakm mRNA only slightly increased upon Mettl3 KO. Therefore, the effect of METTL3 deficiency on Irakm expression was a combination of both transcription and decay but mainly due to decelerated degradation of Irakm mRNAs. Collectively, these data demonstrate that METTL3-mediated m6A modification promotes the TLR4 signaling mainly by accelerating the degradation of Irakm mRNAs.

A novel mechanism has recently been revealed by which m6A methylation facilitates the decay of the chromosome-associated regulatory RNAs (carRNAs), including promoter-associated RNAs (paRNAs), enhancer RNAs (eRNAs), and repeat RNAs, affecting local chromatin state and downstream transcription (39). To assess the potential function of Mettl3 on chromatin openness and nascent transcripts synthesis in BMDMs, we performed deoxyribonuclease I (DNase I)terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick end labeling (TUNEL) and 5-ethynyl uridine (EU) labeling assays in BMDMs from Mettl3flox/flox and Mettl3flox/flox;Lyzm-Cre mice (fig. S7, A and B). Similar chromatin accessibility and nascent transcripts synthesis were observed between WT and Mettl3-deficient BMDMs (fig. S7, A and B). Furthermore, by analyzing the m6A-modified carRNAs in macrophages based on our MeRIP-seq data, we did not identify any significant m6A peaks on paRNA and eRNA upstream of Tnf- and Irakm (fig. S7, C and D), under the conditions that successfully called significant m6A-marked carRNAs for genes such as Vars (fig. S8A). In addition, no significant carRNAs were identified in BMDMs for TLR-related genes, including TRIAP, MyD88, TRAF6, IRAK4, and TRAM (fig. S8, B to E). Further, although carRNAs of Irakm were observed in mouse embryonic stem cells (mESCs) (table S4), no significant Irakm carRNAs were identified in BMDMs of our MeRIP-seq data. In addition, our MeRIP-qPCR results showed that the levels of Irakm carRNAs were largely unchanged with knockout of METTL3 in BMDMs, except for a slight decrease in Irakm eRNA(+), which may account for the slightly increased transcription of Irakm in METTL3-KO BMDMs. Therefore, in contrast to the findings in mESCs, our results demonstrated that in macrophages, m6A regulates TNF-a production by targeting the degradation of Irakm mRNA.

RBPs play a vital role in RNA metabolism, which is tightly connected to all aspects of cellular functions. However, the mechanisms by which RBP-mediated RNA regulation affects the activation of innate immune cells are largely unknown. Here, we have identified METTL3 as a positive regulator of the innate response of macrophages by using pooled RBP CRISPR-Cas9 screens. Specifically, we have demonstrated that METTL3-mediated m6A modification of Irakm mRNA accelerates its degradation, resulting in reprogramming macrophages for activation. These findings provide a previously unappreciated mechanism for epitranscriptional control of innate response in macrophages. Nevertheless, we have not observed high-ranked individual m6A readers in either TNF-Low or TNF-Hi cell population in our pooled RBP CRISPR-Cas9 screening. The functional redundancy of YTHDF proteins appears to exist in the innate immune response of macrophages (33, 34), and our data show that the simultaneous knockdown of Ythdf1, Ythdf2, and Ythdf3, in contrast to knocking down each of these readers individually, can significantly reduce Tnf- expression upon LPS stimulation.

Recent studies have shown that transcripts of key genes of the innate immune signaling pathway are marked by m6A modifications, which are required for the maintenance of proper innate antiviral responses (27, 28, 40, 41) or are essential for dendritic cell activation (26), indicating that the m6A modification is implicated in innate immune responses. Our data document that Mettl3 deficiency in macrophages reduces their proinflammatory cytokine production and thus suppresses their ability to defend against pathogens and eliminate tumors. Thus, the METTL3/m6A modification appears to be required for macrophage activationmediated innate immunity.

Activation of the TLR4 signaling and subsequent induction of effective positive feedback to augment immune response by proinflammatory cytokines has a pivotal role in eliminating invading pathogens. However, the magnitude of the immune response must be tightly regulated to avoid pathologic immune reactions. A previous study has shown that TLR4 activation could negatively regulate the stimulation of macrophages by inducing the expression of Irakm (14). Our data document that Mettl3-KO macrophages have a higher level of IRAKM expression than their WT counterparts, resulting in reduced TLR4 signaling. Except for TLR4 signaling, we observed that Mettl3 deficiency could decrease TNF- expression upon the activation of TLR3 or TLR9 signaling individually. These data support our previously proposed m6A working model in which m6A acts as a gas pedal specifically targeting immediate-early response genes, such as Socs in T cells and Irakm in macrophages, to trigger their rapid degradation and to ensure that the immune cells can quickly respond to the external stimuli and adapt to the environment (24). Later on, these cells increase the expression levels of Socs or Irakm genes to brake the signaling by a feedback mechanism, thus preventing its overactivation.

The MeRIP-seq data demonstrated that Irakm transcripts were marked by m6A modifications, removal of which retarded the degradation of Irakm mRNA, and the resulting excess of IRAKM protein blocked the TLR4 signaling. Thus, Irakm mRNA decay controlled by m6A modification represents a novel mechanism of releasing the brake from the TLR4 signaling pathway. Consistently, our previous study showed that m6A modification selectively targets the transcripts of the SOCS family genes, the gatekeeper of the IL-7/STAT5 signaling pathway, accelerating their degradation necessary to reprogram naive T cells for differentiation and proliferation (24). It was also demonstrated that IRAKM promotes lung tumor growth (42) and fibrosis in multiple organs (15, 43) by skewing macrophage toward an alternative activated phenotype. Mettl3-deficient mice displayed enhanced tumor growth. TAMs and BMDMs from Mettl3flox/flox;Lyzm-Cre mice polarized with either TCM or IL-4 exhibited elevated M2-related markers, suggesting that the balance of macrophage polarization was modulated at an epitranscriptional level by the m6A modification of Irakm mRNA.

A recent study reported that the m6A modification promotes dendritic cell activation by enhancing the translation of target transcripts, CD40, CD80, and Tirap (26). However, our MeRIP-seq data documented that CD40 transcripts were not m6A-marked, indicating that the targets of m6A modification may be cell type specific. Moreover, the m6A peaks of CD80 and Tirap mRNA were not affected in Mettl3-deficient macrophages, suggesting the presence of additional unidentified m6A writer (s) catalyzing the m6A modification of CD80 and Tirap transcripts in macrophages; such a possibility warrants further investigation.

The high ranking of m6A writer genes in our CRISPR screening indicates the fundamental importance of m6A regulation in macrophage activation. It has been recently reported that m6A on carRNAs can globally tune chromatin state and transcription (39). However, neither did we observe a difference in chromatin openness and nascent RNA synthesis between BMDMs from Mettl3flox/flox mice and Mettl3flox/flox;Lyzm-Cre mice, nor did we identify a significant m6A peak on paRNA and eRNA upstream of Tnf- and Irakm. Moreover, no significant carRNAs from TLR-related genes were identified. Therefore, in contrast to the observations in mESCs, our results demonstrated that in macrophages, m6A regulates the levels of TNF- posttranscriptionally, mostly by targeting the degradation of Irakm mRNA. In addition, we found that the m6A levels of carRNAs for Esrrb, Kmt2d, and LINE, which have been proven to be decreased in Mettl3-KO mESCs, were not totally decreased in Mettl3-KO BMDMs (fig. S9). The difference in m6A effects on chromatin status between METTL3-KO mESCs and METTL3-KO BMDMs may reflect differences in cellular contents and environmental context of stimuli-sensitive immune cells versus pluripotent ESCs (21, 34).

In summary, our study demonstrates that m6A modification represents a novel mechanism controlling the innate immune response of macrophages against environmental stimuli. In addition, the obtained results suggest that targeting m6A modulators might be an effective therapeutic approach for inflammatory diseases and cancer.

Mettl3flox/flox mice were generated as previously described (24) and crossed with Lyzm-Cre mice (the Jackson laboratory, Bar Harbor, ME, USA) to obtain CKO mice. The animals were maintained in specific pathogenfree facilities and used according to protocols approved by Animal Care and Use Committees of the Shanghai Jiao Tong University School of Medicine.

Age- and sex-matched Mettl3-WT and Mettl3-KO mice were infected orally with S. typhimurium strain ATCC 14028 at 108 bacteria per mouse. Body weights were monitored daily. Four days after infection, the bacterial burden in the spleen, liver, colon, and feces was determined by counting the colony-forming units (CFU) of the homogenized tissue on MacConkey agar plates.

MC38 murine colon adenocarcinoma cells were provided by Q. Zou, Shanghai Institute of Immunology of Shanghai Jiao Tong University, Shanghai. MC38 cancer cells were injected subcutaneously into 8-week-old female mice (5 105 cells per mouse). Tumor growth was measured as the tumor area.

For the pooled CRISPR screen, we designed 7272 sgRNAs targeting 782 RBPs using CRISPR-FOCUS (http://cistrome.org/crispr-focus/), listed in table S2. sgRNAs were cloned into lenti-puro-guide plasmid following an established protocol (31). Lenti-sgRNA constructs and packaging vectors (pMD2.G and psPAX2) were cotransfected into HEK293T cells, and virus-containing supernatant was collected. Cas9-expressing Raw 264.7 cells were infected with the lentiviral library at an infection rate of 30% and selected with puromycin. Seven days after selection, the infected cells were stimulated with LPS (100 ng/ml) plus brefeldin A for 6 hours and fixed and stained with phycoerythrin (PE)conjugated TNF- antibody for fluorescence-activated cell sorting.

The genomic DNA of cells collected just before sorting or sorted on the basis of TNF- expression was isolated. The sgRNA library was barcoded and amplified with primers listed in table S3 for two rounds of PCR. Amplicons were purified and quantified for sequencing on Illumina HiSeq. The sequencing data generated from the screen and raw sgRNA counts have been submitted to the National Center for Biotechnology Information (NCBI) Database of Gene Expression Omnibus (GEO) Dataset under accession number GSE162469.

Total RNA from Raw 264.7 cells or BMDMs was extracted and enriched in mRNA with Dynabeads mRNA Purification Kit (Thermo Fisher Scientific, Ambion, 61006). mRNAs were then denatured at 95C for 3 min and chilled on ice immediately. A 2-l drop of mRNA was applied directly onto Amersham Hybond-N+ membrane (GE Healthcare, RPN203B) and cross-linked to the membrane by Stratalinker 2400 UV Crosslinker. Unbounded mRNA was washed off with TBST [1 phosphate-buffered saline (PBS) supplemented with 0.02% Tween 20] for 5 min at room temperature and blocked with 5% nonfat milk in TBST for 1 hour at room temperature. The m6A level was determined with an anti-m6A antibody (Synaptic Systems, 202003).

Cells were collected and lysed on ice for 30 min in radio-immunoprecipitation assay buffer containing cocktails of protease and phosphatase inhibitors, and the supernatants were subject to Western blot analysis.

BMDMs and Raw 264.7 cells were stimulated with LPS, IL-4, or TCM along with Golgi inhibitor for the indicated time. Then, single-cell suspensions were prepared from either cultured cells or tumor samples and incubated with antibody cocktails for 15 min at 4C for cell surface staining. For intracellular cytokine staining, cells were fixed with BD Fixation/Permeabilization buffer (BD 554714) for 30 min at 4C and subsequently stained with antibodies for 30 min at 4C. Data were recorded on BD LSRFortessa X-20 and analyzed with FlowJo software.

MC38 cancer cells were cultured in Dulbeccos modified Eagles medium (DMEM) supplemented with 10% fetal bovine serum (FBS) for 72 hours. The supernatant was collected, centrifuged, and stored at 80C for further use.

Bone marrow cells were isolated from the hind leg femur of mice and differentiated into macrophages in DMEM supplemented with 10% FBS (Gibco) and 20% L929 cell culture supernatant for 7 days. Differentiated BMDMs were collected and replated in DMEM without the L929 cell culture supernatant for 12 hours and then stimulated with LPS (Sigma-Aldrich L2880, 10 ng/ml) and IL-4 (PeproTech 214-14-20, 25 ng/ml) for M1 and M2 polarization, respectively.

pLVX-IRES-ZsGreen lentiviral vectors were a gift from Q. Zou (Shanghai Institute of Immunology, China). Lentiviruses encoding Mettl3 and their mutants in pLVX-IRES-ZsGreen plasmids were produced in 293T cells, then collected, filtered through a 0.22-m MCE membrane (Millipore), and used to infect BMDMs. MG-guide retrovirus vectors were a gift from R.A.F. (Department of Immunobiology, Yale University School of Medicine, USA). Retroviruses expressing specific shRNA targeting Irakm in MG-guide plasmids were produced and used to infect BMDMs as described above. The shRNA target Irakm transcripts are listed in table S3. The WT and m6A motif disrupted 3UTRs of Irakm were synthesized and cloned into MG-guide plasmids.

siRNAs targeting Ythdf1, Ythdf2, Ythdf3, and Ythdc1 were transfected into BMDMs using Lipofectamine RNAiMAX (Invitrogen, Carlsbad, CA, USA) according to the manufacturers instructions. The cells were analyzed 48 to 72 hours later. The siRNA sequences are listed in table S3.

The analysis of chromatin openness with DNase ITUNEL assay was performed according to the method of Liu et al. (39). Briefly, BMDMs were permeabilized by 0.1% Triton X-100 in PBS for 10 min before digesting with DNase I (0.2 U/ml; New England Biolabs) and then fixed in 4% paraformaldehyde. Subsequently, the TUNEL assay (DeadEnd Fluorometric TUNEL System, Promega) was performed according to the manufacturers instructions and followed by DAPI staining. Images were captured with an Olympus FV3000 confocal microscope, and the intensity of the nuclear TUNEL signal was quantified using ImageJ software.

Nascent transcripts synthesis was analyzed according to the method of Liu et al. (39). Briefly, BMDMs were cultured on precoated cover glasses. A nascent RNA synthesis assay was conducted 24 hours later using the Click-iT RNA Imaging Kit (Invitrogen, C10329) according to the manufacturers protocol. Images were captured with an Olympus FV3000 confocal microscope, and the intensity of the signal was quantified using ImageJ software.

Nascent transcription rate was analyzed according to the method of Liu et al. (39). Briefly, BMDMs were seeded to the same amount of cells. After 48 hours, EU was added to 0.5 mM at 60, 30, 20, and 10 min before trypsinization collection. Total RNA was purified by TRIzol, and nascent RNA was captured by using Cell-Light EU Nascent RNA Capture Kit (RiboBio). RNA amount and EU adding time were fitted to a linear equation, and the slope was estimated as transcription rate of RNA.

The m6A level of chromosome-associated RNAs was analyzed according to the method of Liu et al. (39). Briefly, total RNA was isolated from the chromosome-associated fraction of BMDMs, and nonribosomal RNA was further enriched by using Ribo-off rRNA Depletion Kit (human/mouse/rat; Vazyme). Fragmentation and MeRIP-qPCR were performed following the protocol in this paper.

RNA purification, reverse transcription, library construction, and sequencing were performed at WuXi NextCODE (Shanghai, China) according to the manufacturers instructions (Illumina). Briefly, polyadenylated mRNA was purified from total RNA using oligo-dTattached magnetic beads and fragmented by the fragmentation buffer. Taking these short fragments as templates, the first-strand cDNA was synthesized using reverse transcriptase and random primers, followed by the second-strand cDNA synthesis. The synthesized cDNA was subjected to end repair, phosphorylation, and A base addition, according to Illuminas library construction protocol. Next, Illumina sequencing adapters were added to both sides of the cDNA fragments. After PCR amplification for DNA enrichment, the target fragments of 200 to 300 base pairs (bp) were cleaned up.

After library construction, Qubit (Thermo Fisher Scientific) was used to quantify the concentration of the resulting sequencing libraries, while the size distribution was determined using the Agilent Bioanalyzer 2100 (Agilent). Then, the Illumina cBot cluster generation system with HiSeq PE Cluster Kits (Illumina) was used to generate clusters. Paired-end sequencing was performed at WuXi NextCODE (Shanghai, China) using an Illumina HiSeq system following the manufacturers protocols for 2 150 paired-end sequencing. These RNA-seq data have been deposited on GEO public database under the accession number GSE162248.

Total RNA from WT or Mettl3-KO Raw 264.7 cells (with or without LPS stimulation) was extracted with the TRIzol reagent (Thermo Fisher Scientific, 15596018), and approximately 100 g of total RNA for each condition was fragmented to ~100 bp in length with fragmentation buffer (10 mM tris-HCl and 10 mM ZnCl2). The RNA size after the fragmentation was validated by 2200 TapeStation detection (Agilent). A sample of 100 ng of the fragmented RNA was saved as the input control, while the remaining RNA was mixed with 50 l of protein A magnetic beads (Thermo Fisher Scientific, 10002D) and 50 l of protein G magnetic beads (Thermo Fisher Scientific, 10004D) premixed with 10 g of anti-m6A antibody (Merck Millipore, ABE572). The samples were incubated for 4 hours at 4C in IP buffer [10 mM tris-HCl, 30 mM NaCl, and 0.1% (v/v) IGEPAL CA-630 supplemented with ribonuclease (RNase) inhibitor]. The beads were washed twice with 1 IP buffer, twice with low-salt IP buffer [50 mM NaCl, 10 mM tris-HCl (pH7.5), and 0.1% IGEPAL CA-630], and twice in 1000 l of high-salt IP buffer [500 mM NaCl, 10 mM tris-HCl (pH7.5), and 0.1% IGEPAL CA-630]. RNA was eluted and purified with the RNeasy kit (QIAGEN) and eluted with 15-l RNase-free water. Both input and enriched RNA samples were used for library preparation with TruSeq Stranded Total RNA Library Prep Human/Mouse/Rat (Illumina) according to the manufacturers instructions.

For MeRIP-qPCR, approximately 1 g of total RNA from WT or Mettl3-KO BMDMs was used. The input and enriched RNA were prepared using the same protocol as described above, but with scaled-down reagents, and dissolved in 10 l of RNase-free water. The enrichment of m6A was analyzed using the LightCycler 480. Myc peak and Myc body were used, respectively, as a positive and negative control for MeRIP-qPCR.

The raw reads were mapped to mouse ribosomal RNA sequences using bowtie2 to remove the reads that came from ribosomal RNA. The unmapped reads were then mapped to the mouse genome (GRCm38.p6 and gencode.vM20) using STAR. The potential bias caused by PCR amplification was removed using the Picard Mark Duplicates command. For m6A-seq data, the fragment coverage of each base of all transcripts was calculated using custom script. The peak calling algorithm was modified from Ma et al. (44). To calculate the enrichment score, the average fragment coverage of the window was used instead of the read count. The m6A level on carRNAs upstream of indicated genes was analyzed according to the method from Liu et al. (39). The m6A RIP-seq data from this study have been deposited to GEO series GSE162254.

BMDMs were seeded on 24-well plates with 1 million cells per well. Actinomycin D was added at a final concentration of 5 M. Cells were collected (after 0, 0.5, 1, 2, and 3 hours), and total RNA was extracted for real-time qPCR. Data were normalized to the t = 0 time point.

pGL4-luc2 (Firefly luciferase) vector of the Dual-Luciferase Reporter Assay System (Promega, E1910) was used to determine the function of m6A modification within the 3UTR of Irakm transcripts. The assay was performed according to the manufactures instruction: Briefly, 100 ng of WT or m6A-mutant IRAKM-3UTR and 25 ng of pRL-TK (Renilla luciferase) control vector were cotransfected into HEK293T cells in triplicates. The relative luciferase activity was accessed 24 to 48 hours after transfection.

All data are presented as means SEM. Comparisons between groups were analyzed by the unpaired two-tailed Students t test or two-way analysis of variance (ANOVA). Statistical analysis was performed using Prism 6 (GraphPad).

Acknowledgments: We thank M. Yang, S. Hu, Y. Zhou, and all other members of the Hua-Bing Li laboratory for discussions and comments. Funding: This work was supported by the National Natural Science Foundation of China (91753141/82030042/32070917 to H.-B.L., 81822021/91842105 to S.Z., 81801550 to J.T., and 81901580 to Y.L.), the Shanghai Science and Technology Committee (grant no. 20JC1417400/201409005500/20JC1410100 to H.-B.L.), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (to H.-B.L.), the start-up fund from the Shanghai Jiao Tong University School of Medicine (to H.-B.L.), the National Key R&D Program of China (2018YFA0508000) (to S.Z.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29030101) (to S.Z.), and the Howard Hughes Medical Institute (to R.A.F.). Author contributions: H.-B.L. conceived the project and designed the research. J.T., X.W., and Y.L. designed and performed the murine portion of the study. H.-B.L., J.T., and X.W. analyzed and interpreted the data and wrote the manuscript. X.R., A.W., and S.Z. performed and analyzed the bacterial infection model. Y.L. and J.Y. generated Mettl3-deficient Raw 264.7 cells, and Y.L., J.Y., and K.M. helped with experiments involving Raw 264.7 cells. Q.Z. provided MC38 cells. Z.C. and Y.Z. helped with analyzing RNA-seq data. W.P., Q.Z., Y.Z., Q.X., J.L., S.Z., R.A.F., and H.-B.L. discussed the projects. This study was supervised by H.-B.L. and R.A.F. All authors read and approved the final manuscript. Competing interests: R.A.F. is a consultant for GSK and Zai Lab Ltd. All other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Sequenced reads have been deposited in the NCBI GEO database (accession nos. GSE162254, GSE162248, and GSE162469). Additional data related to this paper may be requested from the authors.

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Pooled CRISPR screening identifies m6A as a positive regulator of macrophage activation - Science Advances

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How the immune system watches over the brain – Medical News Today

Sunday, February 14th, 2021

Generations of students have learned that the central nervous system has immune privilege. This means that to an extent the immune system tolerates the presence of foreign proteins, or antigens, and tissue in the brain and spinal cord.

The immune system cannot respond in the usual way to infections, injuries, or tumors in the brain and spinal cord, because the blood-brain barrier prevents immune cells from entering or leaving.

Despite this, scientists know that inflammation plays a pivotal role in many neurological and psychiatric conditions, including Alzheimers disease, MS, autism, and schizophrenia.

So the question remains, if there is no exchange of information, how does the immune system respond to and influence the brain in such a broad range of conditions?

A team of scientists led by Washington University School of Medicine in St. Louis, MO, have discovered that immune cells are stationed in the dura mater, which is the tough outer membrane of the brain.

From this vantage point, they monitor the cerebrospinal fluid draining from the brain. If they detect the molecular calling cards of infection, cancer, or injury, they can mount an immune response.

The research appears in the journal Cell.

Every organ in the body is being surveilled by the immune system, says senior author Dr. Jonathan Kipnis, Alan A. and Edith L. Wolff Distinguished Professor of Pathology and Immunology.

He explains:

If there is a tumor, an injury, an infection anywhere in the body, the immune system has to know about it. But people say the exception is the brain; if you have a problem in the brain, the immune system just lets it happen. That never made sense to me. What we have found is that there is indeed immune surveillance of the brain it is just happening outside the brain.

In 2015, a study in mice revealed a network of vessels in the dura mater that drains cerebrospinal fluid from the brain into lymph nodes in the neck. Also in 2015, a study led by Dr. Kipnis recorded similar findings in both mice and humans.

Lymph nodes are part of an extensive network of fluid-filled vessels known as the lymphatic system. An accumulation of pathogens in lymph nodes can lead to the initiation of an immune response.

This suggested a more intimate connection between the brain and immune system than previously suspected. However, it remained unclear exactly where and how immune cells surveil the contents of the cerebrospinal fluid as it drains from the brain.

Dr. Kipnis and his colleagues knew that the lymph vessels that carry fluid from the brain run alongside blood-filled cavities, or sinuses, in the dura mater.

Crucially, the walls of these sinuses are more permeable than the blood vessels of the blood-brain barrier.

Following up this clue, the scientists showed in their experiments that small molecules from the brain and immune cells accumulate in the sinuses.

Some of the cells, known as antigen presenting cells, which include dendritic cells, pick up suspicious molecules and present them to other immune cells, called T cells, which patrol the body in the bloodstream.

When they bind to these suspect molecules, the T cells can initiate an immune response.

Dr. Justin Rustenhoven, a postdoctoral researcher and the first author of the new paper, says the brain must be shielded from the full force of the immune system.

Immune activity in the brain can be highly detrimental, he says. It can kill neurons and cause swelling. The brain cannot tolerate much swelling, because the cranium is a fixed volume. So immune surveillance is pushed to the borders, where the cells can still monitor the brain but do not risk damaging it.

Dr. Kipnis uses a metaphor to explain how immune cells in the dural sinuses monitor the contents of cerebrospinal fluid for unfamiliar proteins or antigens:

Imagine if your neighbors went through your trash every day. If they start finding blood-stained towels in your trash, they know something is wrong. It is the same thing with the immune system. If patrolling immune cells see tumor antigens or signs of infection from the brain, the cells know there is a problem. They will take that evidence to immune headquarters, which is the lymph nodes, and initiate an immune response.

The findings offer promising opportunities for treating brain disorders that involve autoimmune attacks on tissue.

In MS, for example, the immune system degrades the myelin sheath, which is the fatty insulating material that protects nerve cells.

Future treatments could target immune cells in the sinuses of the dura mater to prevent them from initiating certain immune responses in the brain.

Now that we know where it is happening, that opens up lots of new possibilities for modulating the immune system, says Dr. Kipnis.

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How the immune system watches over the brain - Medical News Today

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Immunai raises $60 million to analyze the immune system with AI – VentureBeat

Sunday, February 14th, 2021

Immunai, a startup developing an AI platform to analyze the human immune system, today announced that it raised $60 million. The company says it will use the funds to broaden its functional genomics capabilities and help its partners prioritize, discover, and develop new therapies and drug combinations.

Emerging treatments like gene cell therapies and cancer immunotherapies promise to revolutionize the field of medicine. But the immune systems complexity trillions of cells partitioned into hundreds of types and states that interplay with various systems and proteins threatens to stymie research. In 1999, a patient in a trial died after an immune system attack likely resulting from preexisting antibodies against a virus used as part of gene therapy a death that experts believe led to years lost in gene therapy development. Immunai aims to prevent such mistakes with immune profile-generatingAI.

Immunai was founded in 2018 by Noam Solomon, an ex-Harvard and -MIT postdoctoral researcher, and Luis Voloch, an MIT graduate and former machine learning engineer at Palantir. The two teamed up with members of the Parker Institute, which works with researchers to accelerate the development of immune therapies, to pursue a platform that sheds light on cell populations post- and pre-treatments.

When I met my cofounder Luis, I was a math postdoc at MIT and Luis was working to apply machine learning to biology. Together, we wanted to bring transfer learning AI methods to what we believe would solve the biggest problem in society today disease, Solomon told VentureBeat via email. All disease can be traced back to the immune system. But what Luis and I realized is that pharmaceutical companies dont have access to any comprehensive, granular insight into how the immune system works, how it responds to the drugs or therapies theyre developing, and what patients are most likely to benefit.

Immunais tech records over a terabyte of data from a blood sample, profiling cells at what the company characterizes as unprecedented depth. Samples are compared with a database using AI that maps data to hundreds of cell types and states, creating immune profiles.

Its an approach similar to that of scientists affiliated with the Human Vaccines Project, who are working to identify biomarkers i.e., indicators of particular disease states that predict immune responses to vaccines and cell therapies. Microsoft and startup Adaptive Biotechnologies are also collaborating to develop algorithms that create a translation map for cell receptors to antigens, or pathogen molecules that trigger an immune response, and map those antigens back to diseases.

Clinical studies have traditionally focused on testing thousands or even tens of thousands of subjects and collecting a limited amount of data on each. But massive corpora and AI enable millions of data points to be collected about a single individual.

The immune system is implicated in nearly every illness, making our technology critical for identifying, diagnosing, and treating disease, from cancer to autoimmune disorders, Solomon said in a statement. Our expansion into functional genomics will help our partners tackle their most pressing questions in therapy development, and will ultimately improve the lives of many patients.

Immunais immune profiles could support the discovery of biomarkers by spotting changes in cell type and expression. For example, the Immunai team characterized a CAR-Natural Killer T (NKT) infusion cell therapy product developed at the Baylor College of Medicine for use in neuroblastoma patients. Baylor researchers and Immunai identified a gene potentially involved in CAR-NKT-mediated killing of tumor cells and are working to validate it. Elsewhere, Immunai says its engaging with commercial partners to develop cell therapy candidates in solid tumors.

Voloch says that Immunai is working with 5 of the worlds largest pharma companies in addition to institutions including Stanford, Harvard, Memorial Sloan Kettering, and the University of Pennsylvania. Weve developed a novel platform to reprogram immunity by mining AMICA, our proprietary harmonized single-cell immunology database, with cutting-edge transfer and multi-task learning algorithms, he added. Our vertically integrated functional genomics and AI capabilities allow us to prioritize and validate targets more accurately.

Seventy-employee Immunai is headquartered in New York City, with offices in San Francisco and Tel Aviv. The series A round announced today was led by the Schusterman Foundation, the Duquesne Family, Catalio Capital Management, and Dexcel Pharma. Existing investors Viola Ventures and TLV Partners also participated, bringing Immunais total raised to date to $80 million.

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Immunai raises $60 million to analyze the immune system with AI - VentureBeat

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Dos and don’ts of giving immune system a boost – The New Times

Sunday, February 14th, 2021

Health professionals have raised concerns over a current habit people picked up of over-consuming certain food flavours with the aim of strengthening their immune system, so as to fight the Covid-19 infection. Commonly consumed ones, they say, are ginger, garlic, and lemon.

For instance, youll notice more people taking water with lemon and ginger; either at home or in the office. This, they believe, is one way of fighting the virus as it aids in strengthening immunity.

Private Kamanzi, a nutritionist, says he has observed that many people do this, which is not advisable. Although the above mentioned flavours help in boosting the immune system, when taken in excess and if not well-balanced with other foods, however, could result in health issues.

Unintentionally, one may find themselves overdoing it, or consuming in excess, which is not advisable as it may come with health complications, he warns.

Kamanzi says studies have identified that there is no definite medication for coronavirus, although it has been ascertained that when the immune system is strong, it can fight the virus. And, of course, nutrition plays a big role in boosting immunity.

In this case, he says focusing on just specific foods is not helpful at all; the thing is to ensure you have a balanced diet all through.

For instance, the nutritionist points out that in small doses, ginger has very few side effects while high doseslike more than five grams a dayincreases the chances of side effects.

When it comes to consuming it in excess, ginger can lead to heartburn, diarrhoea, burping, general stomach discomfort, and mouth irritation. Also, some women have reported more menstrual bleeding while taking ginger, he adds.

Studies suggest that over-consumption of garlic has the potential to induce liver damage.

According to a report published by the National Cancer Institute of Unites States (U.S), consuming fresh garlic on an empty stomach could lead to heartburn, nausea, and vomiting.

As per a report published by Harvard Medical School, garlic contains certain compounds that can cause GERD (gastroesophageal reflux disease).

Drinking lemon water on a regular basis can cause enamel erosion or tooth decay because of the acid in the citrus fruit.

Also, too much lemon water can lead to heartburn, nausea, vomiting, and gastroesophageal reflux.

What to consider

Rene Tabaro, a nutritionist at King Faisal Hospital, says diverse research suggests that one way of improving your immunity is through nutrition.

Kamanzi says some of the best foods are proteins as they help improve the cells of the immune system.

Protein is essential to build and repair body tissue and fight viral and bacterial infections. Immune system powerhouses such as antibodies and immune system cells rely on protein, he says.

Too little protein in ones diet may lead to weakness, fatigue, apathy, and poor immunity.

He further notes that a weak immune system also needs carbohydrates for a boost in energy.

However, Kamanzi says, these should be good carbohydrates, for example whole grain breads, beans and cereals and products made from whole wheat flour, and avoid junk or sugary carbohydrates as they weaken the immune system instead of boosting it.

When we are recommending energy foods, we normally emphasise on carbohydrates with less simple sugars, he says.

Tabaro says consuming foods that are rich in vitamins and mineral salts is also ideal. These can be found in fruits and vegetables and facilitate the body to break down the carbohydrates and proteins and absorb them swiftly. This will strengthen the immune system automatically.

Tabaro says the food you eat plays a key role in determining your overall health and immunity. Eat low carb diets, as this will help control high blood sugar and pressure.

Also, focus on a protein-rich diet to keep you in good shape, and regularly consume vegetables and fruits rich in beta carotene (a red-orange pigment found in plants and fruits, especially carrots and colourful vegetables), ascorbic acid (a natural water-soluble vitamin), and other essential vitamins.

editor@newtimesrwanda.com

Original post:
Dos and don'ts of giving immune system a boost - The New Times

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