StemCell Therapy

After receiving a heavy infusion of monoclonal antibodies to treat his bout of Covid-19, President Trump has declared that he is immune to the virus that causes it and talked privately about wearing a Superman T-shirt under his dress shirt when he left the hospital.

Even as the president has exulted in his supposed imperviousness to the coronavirus that is resurging across parts of the country, he has delighted in portraying former Vice President Joseph R. Biden Jr. as vulnerable and cloistered, wearing masks every time you see him.

But even if the president were now immune to the coronavirus, he may not remain so, scientists warn. The presidents unique treatment may have prevented his body from making the antibodies necessary for long-term protection.

The monoclonal antibodies he received were produced by the drug company Regeneron and will wane in a matter of weeks, as the synthetic molecules are known to do. Without replenishment, this decline may leave Mr. Trump even more susceptible to the virus than most patients who have recovered from Covid-19, several experts warned.

Moreover, the steroid treatment the president received early in the course of his illness suppresses the bodys natural immune response, including its propensity to make antibodies of its own.

He may be not protected the second time around, especially because he didnt develop his own antibodies, said Akiko Iwasaki, an immunologist at Yale University.

Most people who are infected with the coronavirus produce antibodies to the virus that should protect them from a second infection. Its unclear how long this immunity lasts; based on research into other coronaviruses, immunity may persist for up to a year, experts have said.

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But Mr. Trumps case is unique.

He announced his diagnosis early on Oct. 2, and a test did not pick up any antibodies in his blood, according to a report released by his physician, Dr. Sean Conley.

The lack of antibodies that early in the course of illness is not unusual. It can take from 10 days to three weeks for powerful antibodies to surface.

If he had tested positive, then we would know for sure that he has his own antibodies, said Dr. Dan Barouch, a virologist at Beth Israel Deaconess Medical Center in Boston.

Since he was antibody-negative, it is less likely but not ruled out, he added. He could have been in the early stage of generating his own antibodies. (Dr. Barouch is an investigator for Regenerons trial of the cocktail for preventing coronavirus infections.)

On Oct. 2, Mr. Trump received eight grams of a cocktail of two monoclonal antibodies made by Regeneron. These antibodies are infused into people like those of Mr. Trumps age, sex and weight who may struggle to produce an immune response of their own.

A test on Oct. 5 confirmed the presence of the antibodies, according to Dr. Conley.

But Dr. Barouch noted that the antibodies detected in the bloodstream are not his antibodies. Theyre antibodies that were administered. Those antibodies will wane over time.

Oct. 16, 2020, 9:19 p.m. ET

The monoclonal antibodies may have quickly suppressed the level of virus in Mr. Trumps body. While this may have protected the president from severe symptoms, it may also have prevented his immune system from making its own antibodies.

If you get the antibodies early on, and you either prevent or rapidly treat infections, Dr. Barouch said, then you probably will actually inhibit the generation of your own bodys antibodies.

Mr. Trump was also treated with dexamethasone, a steroid that is known to suppress the immune system. And he received it much earlier in the course of his illness than usual.

That also may suppress a patients antibody response, said Kartik Chandran, a virologist at Albert Einstein College of Medicine in the Bronx.

Older people and men are already less likely to generate it, he added, referring to antibodies. You add dexamethasone to the mix and God knows.

Mr. Trump received a huge dose of the antibodies, but blood levels are expected to fall by half between 21 to 25 days from infusion. Values in this range are sufficient to support monthly dosing, according to information provided by Regeneron.

The White House did not respond to questions about whether Mr. Trump intends to take monthly doses of the cocktail.

Regeneron has said that it has 50,000 doses of the cocktail in hand, and that it would need to begin rationing the therapy if the drug were to be widely distributed.

In a clinical trial, the drug maker is evaluating whether people given the cocktail make their own antibodies, but has not yet completed the analysis, according to a spokeswoman.

Monoclonal antibodies are generally considered to be safe and effective, but Regenerons cocktail has not yet been rigorously tested in clinical trials. A trial of a monoclonal antibody made by Eli Lilly was paused on Tuesday because of a safety concern.

Mr. Trump has endorsed both treatments and repeatedly declared his immunity to the coronavirus.

Im immune I could come down and start kissing everybody, he said at a rally on Tuesday in Jonesboro, Pa. Ill kiss every guy. Man and woman. Look at that guy, how handsome he is. Ill kiss him. Not with a lot of enjoyment, but thats OK.

Originally posted here:
For How Long Will President Trump Be Immune to the Coronavirus? - The New York Times

Vanderbilt University researchers have reported the counterintuitive discovery that certain chemotherapeutic agents used to treat tumors can have the opposite effect of tissue overgrowth in normal, intact mammary glands, epidermis and hair follicles. The researchers also are the first to report the discovery of an innate immune signaling pathway in fibroblaststhe spindle-shaped cells responsible for wound healing and collagen productionthat causes cells to proliferate. Such signaling pathways previously were attributed only to immune cells.

The article describing the research, DNA Damage Promotes Epithelial Hyperplasia and Fate Mis-specification via Fibroblast Inflammasome Activation, was published in the journal Developmental Cell on Oct. 13.

The findings of this work, led by postdoctoral fellow Lindsey Seldin and Professor and Chair of the Department of Cell and Developmental Biology Ian Macara, have broad implications for diseases associated with the immune system like psoriasis, as well as cancer and stem cell research.

Understanding the functionality of stem cells and the way that their behavior is regulated has been a longstanding research interest for Seldin. Normal stem cells have an amazing ability to continuously divide to maintain tissue function without forming tumors, she explained. We wanted to understand what happens to these cells in their native environment when subjected to damage, and if the response was connected to a specific tissue.

By testing perturbations to the epidermis, mammary gland and hair follicles vis--vis mechanical damage or DNA damage through chemotherapeutic agents, the researchers saw a paradoxical response: Stem cells, which otherwise would divide slowly, instead divided rapidly, promoting tissue overgrowth.

When the tissues were subjected to DNA damage, their stem cells overly proliferated, giving rise to different cells than they normally would. This was a very perplexing result, said Seldin, the papers lead author. We were determined to figure out if this was a direct response by the stem cells themselves or by inductive signals within their environment. The key clue was that stem cells isolated from the body did not behave the same way as in intact tissuean indication that the response must be provoked from signals being sent to the stem cells from other surrounding cell types.

The investigators turned their attention to fibroblasts, the predominant component of the tissue microenvironment. When fibroblasts in the epidermis were removed, the stem cell responsiveness to DNA damage was diminished, indicating that they played an important role. RNA sequencing revealed that fibroblasts can signal by way of inflammasomescomplexes within cells that help tissues respond to stress by clearing damaged cells or pathogens, which also in this case caused stem cells to divide. This is an astounding discovery, said Macara. Inflammasome signaling has previously been attributed only to immune cells, but now it seems that fibroblasts can assume an immune-like nature.

Seldin intends to replicate this work in the mammary gland to determine whether fibroblasts initiate the same innate immune response as in the epidermis, and more broadly how fibroblasts contribute to the development of cancer and other diseases associated with the immune system.

This work was supported by NCI/NIH grants R35CA132898, F32CA213794 and T32CA119925, as well as American Cancer Society grant PF-18-007-01-CCG.

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Vanderbilt researchers make counterintuitive discoveries about immune-like characteristics of cells, chemotherapys impact on tissue growth -...

Reports of reinfection with the coronavirus evoke a nightmarish future: Repeat bouts of illness, impotent vaccines, unrelenting lockdowns a pandemic without an end.

A case study published on Monday, about a 25-year-old man in Nevada, has stoked those fears anew. The man, who was not named, became sicker the second time that he was infected with the virus, a pattern the immune system is supposed to prevent.

But these cases make the news precisely because they are rare, experts said: More than 38 million people worldwide have been infected with the coronavirus, and as of Monday, fewer than five of those cases have been confirmed by scientists to be reinfections.

Thats tiny its like a microliter-sized drop in the bucket, compared to the number of cases that have happened all over the world, said Angela Rasmussen, a virologist at Columbia University in New York.

In most cases, a second bout with the virus produced milder symptoms or none at all. But for at least three people, including one patient in Ecuador, the illness was more severe the second time around than during the first infection. An 89-year-old woman in the Netherlands died during her second illness.

Rare as these cases may be, they do indicate that reinfection is possible, said Akiko Iwasaki, an immunologist at Yale University, who wrote a commentary accompanying the Nevada case study, published in The Lancet Infectious Diseases.

Its important to note that there are people who do get reinfected, and in some of those cases you get worse disease, Dr. Iwasaki said. You still need to keep wearing masks and practice social distancing even if you have recovered once from this infection.

We asked experts what is known about reinfections with the coronavirus, and what the phenomenon means for vaccinations and the course of the pandemic.

First, the good news: Reinfection seems to be vanishingly rare.

Since the first confirmed case of reinfection, reported in Hong Kong on Aug. 24, there have been three published cases; reports of another 20 await scientific review.

But its impossible to know exactly how widespread the phenomenon is. To confirm a case of reinfection, scientists must look for significant differences in the genes of the two coronaviruses causing both illnesses.

In the United States, where testing was a rare resource much of this year, many people were not tested unless they were sick enough to be hospitalized. Even then, their samples were usually not preserved for genetic analysis, making it impossible to confirm suspected reinfections.

A vast majority of people who do get reinfected may go undetected. For example, the man in Hong Kong had no symptoms the second time, and his infection was discovered only because of routine screening at the airport.

There are a lot of people that are going to also have been exposed that arent having symptoms, that were never going to hear about, said Marion Pepper, an immunologist at the University of Washington in Seattle.

People whose second infections are more severe are more likely to be identified, because they return to the hospital. But those are likely to be even rarer, experts said.

If this was a very common event, we would have seen thousands of cases, Dr. Iwasaki said.

Reinfections can occur for any number of reasons: because the initial infection was too mild to produce an immune response, for example, or because the immune system was compromised by other health conditions. On occasion, a patient may be exposed to a large amount of virus that seeded an infection before the immune response could respond.

This variability is entirely expected, experts said, and has been observed in patients with diseases like measles and malaria.

Youll never have the distribution of anything with millions of people where you dont have some very severe rare cases happening at the fringe, said Dr. Michael Mina, a pediatric immunologist at the Harvard T.H. Chan School of Public Health.

At least two of the reinfected patients in Europe had compromised immune systems, for example, and the 89-year-old woman who died was receiving chemotherapy. In other reinfected patients, genetic factors or the lack of certain previous immune exposures may have blunted the bodys ability to fight off a second attack.

There are some people who just dont develop good immune responses to certain pathogens, said Florian Krammer, an immunologist at the Icahn School of Medicine at Mount Sinai. What is causing that? Were not sure, but its rare, usually.

In a vast majority of known infected patients, experts said, the immune system functions as it should against other pathogens.

There are a lot of different infections where you can get re-exposed to the virus, and we would probably not know because you dont have symptoms, Dr. Pepper said. And that might be an important part of boosting immunity.

When the body is exposed to an unfamiliar virus, its normal first to develop some immunity and then to increase that response with each additional exposure. This phenomenon is well known among children, but it is less often seen in adults because they rarely encounter new viruses, Dr. Mina said.

I think its important to recognize that reinfections are literally embedded in the evolution of our immune system, he added. We sometimes lose track of that with so many people talking about this who really havent studied the immune system.

For every confirmed case of reinfection, there are dozens of anecdotal reports of infected people who were sick and seemingly recovered but then became ill again weeks to months later.

Usually there are crucial data missing in those cases, like a confirmed lab diagnosis, or a virus sample that can be sequenced.

The question is always, Is it a real reinfection? Dr. Krammer said. Its very often very challenging to kind of get that kind of data.

A vast majority of these cases are unlikely to be true infections. More likely, these are people experiencing a resurgence of symptoms connected to the original infection. The virus may set off an inflammatory response that can flare up even weeks later and cause symptoms like fatigue and heart problems. In rare cases, some patients may develop a chronic low-grade infection with the virus that never quite goes away.

Even with viruses that can cause acute infections, like flu, Dr. Krammer said, you can have persistent infections if your immune system is sufficiently compromised.

Although these are not real reinfections, they are still worrying if they lead to renewed illness or hospitalization months after the initial infection, Dr. Rasmussen said. If theres recrudescence happening frequently, and people are getting severely ill the second time around, thats potentially its own problem, she said.

Reinfected people without symptoms may still transmit the virus to others. The patient in Hong Kong, for example, was isolated in a hospital even though he had no symptoms. But his viral load was high enough that he could have passed the virus to others.

Obviously, that person wasnt ill, so it bodes well for him, but it doesnt bode well for the community, Dr. Pepper said.

But to be sure of infectiousness, researchers may need to look for live virus. South Korean researchers investigated hundreds of reports of reinfection and were able to rule them out as real cases after failing to grow infectious virus from the samples.

Similar procedures would be needed to rule out the possibility of transmission in each patient, Dr. Rasmussen said, adding, I think thats the only way youd be able to get to the bottom of that.

Reports of reinfection have raised concerns about whether vaccines for the coronavirus will be effective and help communities achieve population immunity. The worry is that the immunity produced by vaccines will not be sufficient in preventing reinfections with the virus.

In reality, experts said, vaccines have a better chance at generating robust immunity than does natural infection with the virus.

For example, the coronavirus is particularly adept at dodging the bodys early immune alarms, buying valuable time to seed an infection. In some people, this lag eventually triggers a cascading immune overreaction that can be more harmful than the infection itself.

Vaccines are intended to unfurl an immune response without interference from the virus, and thus may avoid this inflammatory sequence. Vaccines can also be manipulated to enhance immune memory, in that way producing more lasting, more protective responses.

Vaccine trials are designed to look for an absence of disease, rather than of infection, and its unclear whether vaccines can suppress virus levels enough to prevent transmission to others.

Still, vaccine-induced immunity should perform better than natural immunity, Dr. Rasmussen said, adding, Im optimistic.

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Coronavirus Reinfections Are Real but Very, Very Rare - The New York Times

One of COVID-19's scariest mysteries is why some people are mildly ill or have no symptoms and others rapidly die and scientists are starting to unravel why.

An international team of researchers found that in some people with severe COVID-19, the body goes rogue and attacks one of its own key immune defenses instead of fighting the coronavirus. Most were men, helping to explain why the virus is hitting men harder than women.

And separate research suggests that children fare better than adults thanks to robust first responder immune cells that wane with age.

They're the latest in a list of studies uncovering multiple features of the immune system's intricate cascade that can tip the scales between a good or bad outcome. Next up: Figuring out if all these new clues might offer much-needed ways to intervene.

We have the knowledge and capability of really boosting many aspects of the immune system. But we need to not use the sledge hammer, cautioned Dr. Betsy Herold of New York's Albert Einstein College of Medicine, who co-authored the child study.

Adding to the complexity, people's wildly varying reactions also reflect other factors, such as how healthy they were to begin with and how much of the virus the dose" they were exposed to.

Infection and what happens after infection is a very dynamic thing, said Alessandro Sette, a researcher at the La Jolla Institute for Immunology in San Diego, who is studying yet another piece of the immune response.

IMMUNE PRIMER

There are two main arms of the immune system. Innate immunity is the bodys first line of defense. As soon as the body detects a foreign intruder, key molecules, such as interferons and inflammation-causing cytokines, launch a wide-ranging attack.

Innate immune cells also alert the slower-acting adaptive arm of the immune system, the germ-specific sharpshooters, to gear up. B cells start producing virus-fighting antibodies, the proteins getting so much attention in the vaccine hunt.

But antibodies aren't the whole story. Adaptive immunity's many other ingredients include killer T cells that destroy virus-infected cells and memory T and B cells that remember an infection so they spring into action quicker if they encounter that germ again.

A MISSING PIECE

Usually when a virus invades a cell, proteins called Type I interferons spring into action, defending the cell by interfering with viral growth. But new research shows those crucial molecules were essentially absent in a subset of people with severe COVID-19.

An international project uncovered two reasons. In blood from nearly 1,000 severe COVID-19 patients, researchers found 1 in 10 had what are called auto-antibodies antibodies that mistakenly attack those needed virus fighters. Especially surprising, autoimmune disorders tend to be more common in women but 95% of these COVID-19 patients were men.

The researchers didn't find the damaging molecules in patients with mild or asymptomatic COVID-19.

In another 660 severely ill patients, the same team found 3.5% had gene mutations that didn't produce Type I interferons.

Each of those silent vulnerabilities was enough to tip the balance in favor of the virus early on, said Dr. Jean-Laurent Casanova, an infectious disease geneticist at Rockefeller University in New York, who co-leads the COVID Human Genetic Effort.

Certain interferons are used as medicines and are under study as a possible COVID-19 treatment; the auto-antibody discovery adds another factor to consider.

KIDS' IMMUNITY REVS FAST

It's not clear why children appear less at risk from COVID-19. But occasionally they're sick enough for hospitalization, giving Herold's team the opportunity to compare 60 adults and 65 children and teens at New Yorks Montefiore Health System.

The children produced much higher levels of certain cytokines that are among the innate immune system's first responders. When the immune system's next stage kicked in, both adults and children made antibodies targeting the coronavirus. Here's the rub: The adults' adaptive immune response was more the type that can trigger an inflammatory overreaction.

The findings suggest kids' early robust reaction lets their immune system get ahead of the virus, making an overreaction less likely "and that's protecting them, Herold said.

ANY PREEXISTING IMMUNITY?

The coronavirus that causes COVID-19 is new to humans. But Sette's team studied blood samples that were stored in freezers before the pandemic and found some harbored memory T cells that recognized a tiny portion of the new virus in laboratory tests.

You can actually tell that this is an experienced T cell. This has seen combat before, Sette said. Researchers in Germany, Britain and other countries have made similar findings.

The new coronavirus has cousins that cause as many as 30% of common colds, so researchers believe those T cells could be remnants from past colds.

But despite the speculation, we don't know yet that having those T cells makes any difference in who gets seriously sick with COVID-19, noted Rory de Vries, co-author of a study in the Netherlands that also found such T cells in old blood.

All these findings beg for a deeper understanding of the myriad ways some people can be more susceptible than others.

We need to look quite broadly and not jump into premature conclusions about any one particular facet of the immune system, said Stanford University immunologist Bali Pulendran. He also has found some innate immune cells in a state of hibernation in seriously ill adults and next is looking for differences before and after people get sick.

But, it's not just all about the immune system, cautioned Dr. Anita McElroy, a viral immunity expert at the University of Pittsburgh Medical Center whos closely watching the research. A way to tell in advance who's most at risk? Were a long, long way from that.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institutes Department of Science Education. The AP is solely responsible for all content.

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Mild to severe: Immune system holds clues to virus reaction - ABC News

Your immune system stands between you and deadly infections. But as you get older so does your immune age, making you more susceptible to disease. Fortunately, we are discovering plenty of things you can do to turn back the clock and stay healthy. In this episode of our video series Science with Sam, find out how your immune system works and how you can give it a boost.

Tune in every week toyoutube.com/newscientistfor a new episode, or check back tonewscientist.com

One of the most important things standing between you and a deadly infection is your immune system the intricate, biological defence mechanism that protects your body from harmful invaders. And theres a lot we can do to give our immune system a helping hand.

Your immune system is made up of two divisions: the innate immune system and the adaptive immune system, each with its own battalion of specialist cells and defensive weapons.

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The innate immune system is the first line of defence. Its made up of cells like the scary-sounding macrophage, and the less scary-sounding neutrophil. These general-purpose guards patrol the bloodstream on the lookout for anything that shouldnt be there. When they detect an intruder, they neutralise the threat by engulfing it like Pac-Man, spraying it with deadly chemicals or suicidally expelling their DNA and throwing it around the invader like a net.

Then theres the adaptive immune system, which you can think of as the immune systems special forces, elite agents trained to fight specific pathogens. Unlike the innate system, which can attack any invading cell or virus, these cells are only effective against one enemy, and they must be trained to fight them first.

B cells fight bacteria and viruses by making Y-shaped proteins called antibodies that neutralise an invader or tag it for attack by other parts of the immune system.

Then there are T cells. These coordinate and carry out attacks on infected cells. Helper T Cells call in reinforcements by sending out chemical messages known as cytokines. Killer T-Cells are the front line soldiers, trained, as the name suggests, to destroy the enemy.

When we encounter a disease for the first time, it takes a while for the adaptive immune system to learn how to fight it. But once its up and running, it creates a memory, allowing a fast and brutal response to future infections often neutralising it before you even notice. This is the premise of vaccines and the reason why you only get diseases like chicken pox once.

If you want to know more about vaccines, theres a video all about them, just hit the link at the end of this video. Better yet, subscribe to New Scientist today and get 20 per cent off if you enter the code SAM20 at checkout.

Your immune system works so well that, most of the time, you wont even notice it. But it weakens as you get older, making you more susceptible to infection. Thats a key reason why people over the age of 70 are most vulnerable to diseases like covid-19, or even the flu.

This decline happens to all of us, but it can be accelerated by lifestyle factors like smoking and inactivity. Obesity is also linked to a faster decline in immune potency.

All of which means that, although the strength of your immune system is linked to your age, a 40-year-old can have the immune system of a 60-year-old. Or on the flipside, a healthy 60-year-old may have the immune system of a 40-year-old.

Scientists have recently developed ways to measure your immune age. Fortunately, it turns out your immune age can go down as well as up. And there are some simple ways to turn back the clock on your immune system.

As we get older, some of our immune cells start to misbehave. Take neutrophils, those early responder cells. As they age, they get worse at hunting down intruders, blundering through your tissues, causing damage.

The root of the problem is an overactive enzyme involved in their sense of direction. Dialling down that enzyme rejuvenates the neutrophils so they know where theyre going. And theres a simple, drug-free way to do it: exercise.

One study in older adults showed that those who got 10,000 steps a day on average had neutrophils as good as a young adult.

Exercise also has benefits for your T cells. Before they are released onto active duty, T-cells mature in a little-known organ called the thymus gland in your chest. The thymus degenerates over time, resulting in a drop-off in the number of T cells.

Physical activity has a huge effect on the rate of this degeneration. A study found that amateur cyclists aged between 55 and 79 had youthful thymus glands and their T-cell counts were similar to those of much younger people.

Another key factor in your immune age is your gut bacteria. There is good evidence that poor gut health is a cause of premature ageing and that a healthy microbiome can reduce your immune age. Eating a healthy, varied diet rich in fibre, plant matter and fermented foods can help maintain a healthy community of gut microbes.

Your body has a highly evolved, intricate defence system thats effective at keeping you well, but only if you look after it.

I dont know about you but Ive been a bit less active of late, so Im considering this something of a wake-up call.

Looking after your immune system is a no-brainer, and its as easy as a walk in the park.

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The immune system: How to boost it and lower your immune age - New Scientist News

A type of the immune systems T cells known to fight against bacterial infections is strongly activated in people with moderate to severe Covid-19, according to a study which provides a better understanding of how the body responds to the novel coronavirus infection.

Researchers, including those from the Karolinska Institutet in Sweden, noted that this component of the immune system called MAIT cells make up about one to five percent of T cells in the blood of healthy people, and are primarily important for controlling bacteria, but can also be recruited to fight some viral infections.

They explained that T cells are a type of white blood cells that are specialised in recognizing infected cells, and are an essential part of the immune system. In the current study, published in the journal Science Immunology, the scientists assessed the role played by MAIT cells in Covid-19 disease.

They examined the presence and character of MAIT cells in blood samples from 24 patients admitted to Karolinska University Hospital with moderate to severe Covid-19 disease, and compared these with blood samples from 14 healthy controls and 45 individuals who had recovered from Covid-19. Four of the patients died in the hospital, the study noted.

To find potential treatments against Covid-19, it is important to understand in detail how our immune system reacts, and in some cases, perhaps contribute to worsening the disease, said Johan Sandberg, a co-author of the study at Karolinska Institutet.

According to the study, the number of MAIT cells in the blood decline sharply in patients with moderate or severe Covid-19, and the remaining cells in circulation are highly activated.

Based on these results, the scientists suggested that the MAIT cells are engaged in the immune response against the novel coronavirus SARS-CoV-2. This pattern of reduced number and activation in the blood is stronger for MAIT cells than for other T cells, they said. The study also noted that pro-inflammatory MAIT cells accumulated in the airways of Covid-19 patients to a larger degree than in healthy people.

Taken together, these analyses indicate that the reduced number of MAIT cells in the blood of Covid-19 patients is at least partly due increased accumulation in the airways, Sandberg said.

The scientists added that the number of MAIT cells in the blood of convalescent Covid-19 patients recovered at least partially in the weeks after disease, which can be important for managing bacterial infections in individuals who have had Covid-19. They said the MAIT cells tended to be extremely activated in the patients who died.

The findings of our study show that the MAIT cells are highly engaged in the immunological response against Covid-19, Sandberg said. The scientists believe the characteristics of MAIT cells make them engaged early on in both the systemic immune response, and in the local immune response in the airways to which they are recruited from the blood by inflammatory signals.

There, they are likely to contribute to the fast, innate immune response against the virus. In some people with Covid-19, the activation of MAIT cells becomes excessive and this correlates with severe disease, Sandberg added.

(This story has been published from a wire agency feed without modifications to the text.)

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Strong activation of anti-bacterial cells of immune system linked to severe Covid-19: Study - Hindustan Times

29Sep2020

Optogenetics researchers in Switzerland and US have optically stimulated nerve fibers in living mice.

Through this process, they have demonstrated that the nervous system has a direct influence on the immune system.

Over the past ten years, a new method has literally shed more light on the brain: optogenetics allows scientists to dstimulate genetically-modified nerve cells and investigate their functioning within the complex network inside the skull. This technique represents a revolution in neuroscience, say the Swiss-US team, but to date, it could only be applied to study the central nervous system, and not the peripheral nervous system.

A team of electrical engineers led by Qiuting Huang, a professor at the Institute for Integrated Systems at ETH Zurich, have developed a system that connects implantable LEDs with a tiny device on the subjects head which can be controlled from a tablet via Bluetooth. They have stimulated, with great precision, nerve fibers in the bodies of freely-moving mice, as the scientists report in Nature Biotechnology.

Our goal was to develop an integrated platform as small as possible. Together, the chip, the battery and the antenna for wireless signal transmission weigh less than one gram and occupy less than one cubic centimetre, explained Huang.

While the chip technology enables high integration density of electronic circuits, there are limits to miniaturization, particularly with batteries; the smaller the volume, the greater the energy density. This, in turn, increases the risk that batteries might ignite.

The team originally intended to develop this platform for a project to measure oxygen saturation and blood pressure, but right from the outset of the design phase, they endeavored to ensure the widest possible application for the chip.

Because our system is programmable, we were able to take the electronic circuits that we had been intending to use to measure oxygen saturation in blood and re-purpose them to control the implanted light emitting diodes, said contributing scientist Philipp Schnle.

The group has been collaborating with Stphanie Lacours group at EPFL for five years. Our sophisticated electronics and their soft bioelectronic sensors were made for each other, said Huang. Advances in material sciences and electronics build on each other and interconnect with each other. Together, we have developed an approach that allows us to stimulate a specific nerve fiber in the body of the mouse at precise points in time, added Schnle.

At Harvard Medical School, a research group led by Clifford Woolf wrapped the implants around the sciatic nerve. Without damaging the nerve, over several days, they managed to repeatedly use blue light flashes to activate specific nerve cells known as the nociceptors, which specialize in the transmission of pain signals.

To their surprise, the researchers discovered that repeated optical stimulation of these nociceptors produced a slight reddening in one of the mouses hind paws, a clear sign of inflammation.

Scientists had previously assumed that pain and inflammation were two different processes that arose independently. But now we have been able to prove conclusively that the neurons responsible for pain sensations can also generate an inflammatory immune response, said Woolf. As the researchers explain in the Nature Biotechnology article, these results may potentially point the way to new approaches in such areas as the treatment of chronic pain, or persistent inflammation.

Huang believes that electrical engineering will play an increasingly important role in human health in the future. He highlights the term electroceuticals a combination of electronics and pharmaceuticals which is already being discussed among experts.

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ETHZ-led group shows that nervous system directly influences immune system - Optics.org

Despite the availability of multiple FDA-approved immunotherapies that leverage the bodys immune system to fight cancer, only a fraction of cancer patients are benefiting. That's because cancer cells are cunning. They develop strategies to avoid being targeted and destroyed by immune cells.

To understand the genetic drivers behind the ability of cancer cells to evade the immune system, scientists at the University of Toronto, in collaboration with Agios Pharmaceuticals, used CRISPR to screen six genetically diverse mouse cancer cell lines. They found that genes involved in autophagya process where cells recycle damaged components to regenerate themselveswere key for immune evasion.

The researchers suggested that their findings, published in Nature, open up new venues for the development of immunotherapies that could be effective for largepatient populations across several different tumor types.

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Its very important to understand at the molecular level how cancer develops resistance to immunotherapies in order to make them more broadly available, saidUniversity of Toronto professor Jason Moffat, Ph.D., the studys corresponding author, in a statement.

Moffat and colleagues used CRISPR to screen cancer cells that were cultured in the presence or absence of preactivated killer T cellsimmune cells with a natural ability to hunt and kill cancer. They identified 182 genes that, when deleted, increased either the sensitivity or theresistance of cancer cells to T cells. They called them core cancer-intrinsic cytotoxic T lymphocyte-evasion genes, becauseevery one of them was present across at least three of the six cells lines that the team screened.

The core set of genes included several genes that were known to affect signaling of interferon gamma, a cytokine thats critical to an array of immune responses and that serves as a master communicator with several types of immune cells. Three negative regulators of the interferon-gamma responseSocs1, Ptpn2 and Adaralso emerged as immune-evasion genes.

Several genes identified were related to autophagy. Among the top hits was the Fitm2 gene, which is required for normal fat storage in adipose tissue in mice but was not previously associated with interferon-gamma signaling.

RELATED:New strategies for improving pancreatic cancer treatments

In two mouse models of renal cell carcinoma and melanoma, cancer cells with deleted Fitm2 showed increased cell death after treatment with interferon gamma compared with control cells, the team reported.

Surprisingly, the researchers also found that deleting certain autophagy genes in pairs could make the cells resist T-cell killing. For example, cells that lacked both Atg12 and Atg5 were strongly resistant to the killing effects of T cells as compared with single-mutant cells. This means that if a tumor already harbors a mutation in one autophagy gene, an immunotherapy that targets another autophagy gene could make the disease worse, the researchers explained.

Other oncology researchers are also focusing on the autophagy. A team from the University of Cincinnati, for example, found that mutations in mitochondrial complex I could prevent the autophagy thats triggered by mTOR inhibitors. And researchers at the University of North Carolina reported that targeting the KRAS mutation in pancreatic cancer with an MEK inhibitor made cancer cells more dependent on autophagy for survival. They blocked the process with the anti-malaria drug hydroxychloroquine.

The University of Toronto-led team believes its list of 182 core immune-evasion genes may inform efforts to develop novel cancer immunotherapies. The scientists stressed the need to explorehow combined genetic interactions may alter cancers immune-evasion activity. While simultaneous control of certain genetic features may sensitize cancer cells to immunotherapy, it could make the disease worse in others, they warned.

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Agios helps identify genes that allow cancer to escape the immune system - FierceBiotech

Cannabis is celebrated for the benefits it offers in the management of certain medical conditions. As awareness around cannabis grows, consumers are becoming better versed in the therapeutic potential of cannabinoids in the treatment of specific autoimmune diseases, inflammation, and gastrointestinal disorders.

But how does cannabis affect the immune system as a whole? If youre a regular consumer, you may have pondered whether cannabis weakens or boosts your immune system. Can frequent cannabis use render you more prone to infections or contagious diseases?

As it turns out, research into cannabis and the immune system hasnt historically piqued the interest of scientists. However, as our understanding of the effects of cannabis on the body becomes more sophisticated, we need to also broaden our knowledge of how cannabis influences the immune system.

Present evidence suggests that cannabis can suppress immune system function. While this can be helpful for individuals with autoimmune illnesses, it may not be so beneficial for those with functional immune systems.

The immune system is one of the bodys most sophisticated networks. A collection of specialized cells, endogenous chemicals, and organs work in concert to ward off pathogens and infections, protecting the health and homeostasis of the body.

The immune system is multifaceted, and its core components that actively combat infection include white blood cells, the complement system, antibodies, the lymphatic system, the spleen, the thymus, and bone marrow, but well mainly talk about white blood cells.

Memories of every microbe previously defeated by the immune system are logged in white blood cells. These memories enable the fast tracking and elimination of infections that have already been experienced. The immune system is also responsible for detecting and eradicating malfunctioning cells.

The knowledge we have about the interaction of cannabis with specific immune elements is limited. While there is some research exploring the effects of cannabinoids on white blood cell count and the lymphatic system, we know less about how cannabis impacts the thymus or the complement system.

An elegant connection exists between the bodys endocannabinoid system (ECS) and its immune system. The ECS is generally considered to be one of the gate-keepers of the immune system, preventing the onset of overwhelming inflammatory responses that may result in disease. The ECS can also influence the function of immune cells.

CB1 and CB2 receptors in the endocannabinoid system mediate the effects of cannabis within the immune system. The two major cannabinoids, THC and CBD, appear to have distinctive effects on the immune system due to their unique interactions with cannabinoid receptors. Abundant literature suggests that cannabinoids affect the functions of most types of immune cells.

A 2020 review found robust evidence that CBD suppresses certain inflammatory responses in the immune system and may induce cellular death in immune cells. Immune cell death isnt always a bad thingits a normal part of the cellular life cycle, and helps to protect a person by alleviating inflammatory responses.

Like CBD, THC also suppresses immune activity, dialing down inflammatory responses. THC has also been shown to alter the function of immune cells responsible for antimicrobial activity.

When scientists discuss cannabis and the immune system, they often discuss its effects as immunomodulatory or immunosuppressive. Immunomodulation refers to any therapy that modifies the immune system response. When cannabis suppresses the expression of aspects of the immune system, this form of modulation is known as immunosuppression.

Its vital to point out here that marijuanas ability to subdue or suppress immune system cells can be useful if the immune system is dysregulated and in need of suppression. If not, immune suppression might not be helpful.

Research published in 2017 indicated that both CBD and THC have an immunomodulatory effect on the human intestinal lymphatic system, the major host of immune cells. The lymphatic system also contains more than half the bodys lymphocyteswhite blood cells that play a critical role in finding and destroying foreign cells or substances that have infiltrated the body.

The studys authors found that oral administration of CBD and THC with fats resulted in extremely high cannabinoid levels in the intestinal lymphatic system: CBD concentrations in lymph cells were 250 times higher than in plasma, while THC concentrations in lymph cells were 100 times higher than in plasma.

So, whats the significance of this? For individuals with autoimmune diseases, cannabis can achieve higher concentrations in the lymphatic system and suppress unhealthy inflammatory immune responses more successfully.

While the immunosuppressive properties of cannabis may be just what the doctor ordered for autoimmune patients, they can cause problems for other cannabis users.

Research carried out in 2003 on healthy volunteers suggests that regular cannabis may subdue immune function. Cannabis users were found to have fewer proinflammatory cells and more anti-inflammatory cells.

While less potential for inflammation may sound like a win, in this case, it was associated with a significant reduction in white cell functionality, and impaired white cells can mean a hindered ability to fight off infections. Regular cannabis users also had decreased amounts of natural killer cells, which limit the spread of tumors and microbial infections.

The study also indicated that there may be a dose-response relationship between cannabis use over an individuals lifetime, and a decrease in certain immune system markers, meaning those who use cannabis regularly may be more susceptible to the progression of infectious disease.

What about the effects of cannabis on extremely immunocompromised individuals? Unfortunately, cannabis can substantially decrease infection-fighting cells in people undergoing chemotherapy. This suppressive response may further add to the detrimental effects of chemotherapy on immune systems of those with cancer.

Research on people with HIV+ and AIDS, who are particularly vulnerable to infections, however, indicates that there is no firm evidence that cannabis adversely affects immune function.

Instead, findings suggest cannabis use among HIV+ patients may enhance the immune system by producing a statistically significant decrease in viral load and an increase in CD4 cells. CD4 cells can be considered a marker that indicate the robustness of the immune system.

While existing research allows us to glean insights into cannabis and the immune system, we need more rigorous data to paint broad brushstrokes. According to the most recent 2017 report from the National Academies of Science, Engineering, and Medicine (NASEM), theres insufficient research on the effects of cannabis or cannabinoid-based medicines on the human immune system to draw firm conclusions.

Within the current global climate shaped by COVID-19, theres an impulse among the research community to enhance our understanding of the impact of cannabis on the immune system. Some cannabis researchers are currently channeling their focus into investigating whether cannabis may be helpful or harmful in treating COVID-19.

More profound exploration into the effects of cannabinoids on the immune system is also being encouraged. Watch this space as new frontiers are forged.

Emma Stone is a journalist based in New Zealand specializing in cannabis, health, and well-being. She has a Ph.D. in sociology and has worked as a researcher and lecturer, but loves being a writer most of all. She would happily spend her days writing, reading, wandering outdoors, eating and swimming.

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Does cannabis help or hurt the immune system? - Leafly

Drugs currentlyused to keep the HIV virus in check also cause immune-system changesthat mightmake humans better able toresist viral infectionsbutmight also cause harmful inflammation, according to a study published today in Cell Reports Medicine.

The UW Medicine-led studyby Dr.Florian Hladik and Sean Hughes examined the effects ofa commonly prescribed drug cocktail of drugs on the body.

Sold under the brand name Truvada, tenofovir disoproxil fumarate and emtricitabine (TDF/FTC)are prescribed in tandem formost HIV/AIDS patients to suppress viral loads to undetectable levels. First allowed for use in the United States 20 years ago, the drugs haveenabledpeopleto live for decades beyond their initial diagnosis.

However, Hladik said,"the virus itself never goes away."

In this research, the investigatorsstudied the effect of TDF/FTC in patients who were using the drugto prevent HIV, and in the absence of active HIV infection. The researchers observed patientsover the past five yearsand also includeddata from two earlier studies.

We wanted to know how the drugs themselves affect the immune system, Hughes said. We found that they stimulated type I / III interferon responses, a part of the immune system that is crucial for the bodys ability to fight off viruses. This only happened in the gut.

The clinical consequences of the findings are uncertain and merit further study.

Increased type I / III interferons could be a good thing and actually make the drugs more effective at suppressing viral infections, including HIV. However, they could also cause inflammation, which could contribute to conditions such as cardiovascular disease that are common in people living with HIV, Hladik said. These effects might even make it harder to find a cure for HIV if they make cells silently infected with HIV (called latent cells) more likely to survive or even cause them to proliferate.

Hladik and Hughesalso want to look for those same effects in people infected with HIV.

New drug regimens have just become available that highly suppress the HIV virus in patients and dont contain TDF/FTC or other drugs of thatclass. Bothhope to conduct a trial comparing immunity in HIV-infected individuals using TDF/FTC to others using these newer regimens to determine whether their findings are true in HIV-infected individuals. The researchers hypothesize that the newer regimens will avoid chronic immune activation and decrease the number of latent cells.

The most important next step is to repeat our studies in HIV-infected individuals, and to find out if replacing drugs such as TDF/FTC with newer regimens has clinically relevant effects on reducing chronic inflammation and persistence of latent HIV, Hladik said.

This work was funded by the National Institutes of Health(R01AI116292, R01AI111738,R01AI134293,AI027757,AI069481,R01DK112254);the Bill and Melinda Gates Foundation;the Microbicide Trials Network (UM1AI068633); the Canadian Institutes for Health Research;the Emory University-CDC HIV/AIDS Clinical Trials Unit (UM1AI069418, from the NIAID). The ddPCR work was supported by a grant from the James B. Pendleton Charitable Trust. A National Cancer Institute grant supported the Fred Hutchinson Cancer Research Center Experimental Histopathology core facility.

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Common HIV drugs increase a type of immunity in the gut - UW Medicine Newsroom

Amid the rush to test and develop potential treatments for COVID-19, lab-made antibodies are showing hints of success. In news releases, two companies announced preliminary results, though shared only limited data, that suggest the experimental drugs may help patients both early and late in infection.

One clinical trial of monoclonal antibodies human-made versions of immune system defenders produced by the body suggests that the drugs can help keep people hospitalized with COVID-19 from needing a ventilator or from dying. And a second trial appears to show that the drugs can bring down levels of the coronavirus in recently infected people, and help reduce the chances that a person would need hospitalization.

Antibodies are part of the bodys natural defense against infectious pathogens. The proteins typically attach to parts of bacteria or viruses to fight off infection. In the lab, scientists can engineer versions of antibodies to recognize specific targets in order to hinder the virus replication or prevent the bodys immune system from overreacting to the virus (SN: 2/21/20).

A monoclonal antibody drug called tocilizumab is one of the latter types; it blocks a part of the immune response that can cause inflammation, a protein known as IL-6. By curbing inflammation, the drug could help people whose immune systems have become overactive through a process called a cytokine storm, which can cause severe COVID-19 symptoms (SN: 8/6/20).

In a Phase III clinical trial of 389 people hospitalized with COVID-19, those who received tocilizumab were 44 percent less likely to need a ventilator or die compared with people who got a placebo, San Franciscobased biotechnology company Genentech announced September 17 in a news release. Of those who received the drug, 12.2 percent of people needed a ventilator or died, compared with 19.3 percent of patients who received a placebo. Still, when the researchers looked at death alone, the drug did not result in a statistically significant difference in mortality between the groups.

Saying that it was still analyzing the data, the company did not provide such specifics as how many people died in each group.

A 44-percent decrease is definitely very intriguing, says Abhijit Duggal, a critical care specialist at the Cleveland Clinic who has treated people with COVID-19. But because the results have been publicized in a news release, without key patient information, I dont know what to really make of that, Duggal says. Only as more data come in will experts be able to conclusively say whether the drug might help people, he says. The announced results have not yet been vetted by outside experts or published in a peer-reviewed journal.

Unlike many other clinical trials of potential COVID-19 drugs and treatments, the Genentech trial focused on groups of people that have been disproportionately impacted by the virus (SN: 4/10/20). Around 85 percent of people in the study are Black, Hispanic and Native American. People in these groups are more likely than white people to be infected or die from COVID-19, studies have shown. In part thats due to high rates of underlying conditions like high blood pressure and jobs with a higher risk of exposure to the virus.

Its really important that [the researchers] are including a diverse population, says Rajesh Gandhi, an infectious disease physician at Massachusetts General Hospital and Harvard Medical School in Boston. That is critical as we do these trials.

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In a previous Genentech-related trial that included 452 people with severe COVID-19, tocilizumab did not help improve symptoms or prevent death, researchers reported in a preliminary study posted September 12 at medRxiv.org. Other trials of the drug have reported improved outcomes in people with moderate or severe COVID-19 symptoms.

Importantly, the new trial focused on hospitalized people before they required a ventilator, says Jamie Freedman, Genentechs head of U.S. medical affairs. So differences among trials could be a timing issue. If you give it too early, before cytokines are elevated, would there be a benefit there? When patients are already in the ICU, is it too late? Or is there some sweet spot in the middle? Freedman says. Those are analyses that really need to continue.

Scientists working on another monoclonal antibody, which targets the coronavirus spike protein, also recently reported promising results (SN: 2/21/20). Called LY-CoV555, the drug can reduce the amount of virus in the bodies in newly infected people and help prevent COVID-19 hospitalizations, Indianapolis-based pharmaceutical company Eli Lilly announced September 16 in a news release.

People in this ongoing Phase II clinical trial to determine efficacy receive either a low, medium or high dose of the antibody or a placebo. So far, those who get a medium dose of LY-CoV555, which is based on an antibody from one of the first COVID-19 patients in the United States, appear to clear the virus faster than those on the placebo, according to the release. Fewer treated patients still had high viral loads later on in the study. Most people, including those on a placebo, cleared the virus from their bodies by day 11. Like Genentech, Eli Lilly released only limited data. The announced results have not yet been vetted by outside experts or published in a peer-reviewed journal.

Its really intriguing and tantalizing information, Gandhi says. But without the full details of the study, like patient age or whether any people had underlying conditions, its difficult to know how solid the findings are, he says.

Its surprising that people on the medium dose had a benefit from the drug but those on the higher dose didnt, but that could be because the results are preliminary and could change as people are added to the trial, says Nina Luning Prak, an immunologist at the University of Pennsylvania. But in principle, it looks hopeful, she says.

Whats more, of 302 people treated with any amount of LY-CoV555, five, or 1.7 percent, landed in the hospital, while nine people, or 6 percent, in a control group of 150 patients who received a placebo, were hospitalized. Its unclear based on the results included in the news release, however, whether the difference between the two groups is meaningful. But if its borne out, well see hopefully soon that this is important because it shows that an antibody is having an antiviral effect, Gandhi says.

There are many other monoclonal antibody trials ongoing around the world, many of which feature drugs that bind to a variety of both virus and host proteins. Experts are carefully watching for results, keen to know for sure whether such treatments can help patients. Still, compared with where treatments were in March and April, weve made progress, Gandhi says. I think that progress is going to just accelerate.

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Antibodies made in the lab show some promise for treating COVID-19 - Science News

Its unusual that a virus would be less severe in children than it is in adults. But when it comes to COVID-19, kids make up just a small percentage of severe cases. Yale researchers are working to understand why that is.

Their discoveries can help guide understanding of the virus and possible treatment options.

Ina paper published recently in Proceedings of the National Academy of Sciences(PNAS),Dr. Naftali Kaminski, theBoehringer-Ingelheim Endowed Professor of Internal Medicine and chief of Pulmonary, Critical Care and Sleep Medicine, and colleagues shared findings related tochildrens surprising immunity to the virus. They detailed how factors including allergies, asthma, the common cold, and existing vaccines may be having a protective effect.

Meanwhile,Carrie Lucas, assistant professor of immunobiology at Yale, is looking at blood samples from the small percentage of children who develop the rare condition known as Multi-Inflammatory Syndrome in Children, or MIS-C, in response to COVID-19. Her lab is analyzing blood samples for molecular and genetic clues to figure out why a certain subset of kids are most at risk.

Findings just published in the journal Science Translational Medicine led byKevan Herold, the C.N.H. Long Professor of Immunology and Internal Medicine at Yale, revealed that children diagnosed with COVID-19 express higher levels of two specific immune system molecules, a factor that might be leading to better health outcomes.

Related story:Childrens immune response more effective against COVID-19

Understanding why children appear to be better protected from severe cases than adults could provide important clues on how the novel coronavirus spreads, who is at greatest risk, and how to treat it.

This is different from other viruses that affect kids more seriously, Kaminski said. Its an interesting conundrum and could provide implications for therapeutics.

In the PNAS paper, researchers point to the possibility that allergies and asthma in children has a protective effect. When the body responds to an allergy or asthma trigger, the immune system releases Th2 cells, which in turn increases a type of cell called the eosinophil in the blood and tissues. This allergic inflammation has been shown to dramatically reduce the levels of a key receptor to the COVID-19 molecule, known as ACE2. They added that astudy of 85 older adultswho died of COVID-19 in China showed that they had very low levels of blood eosinophils.

Initially, there was a concern about the impact of COVID-19 on children with asthma, said Kaminski. Some 7.5% of U.S. children under 18, or 5.5 million kids, have asthma, according to the Centers for Disease Control and Prevention. But, in fact, it seems that compared to other chronic lung diseases, people with asthma are infected less, and, when they are infected, asthma is not a risk factor.

Instead, risk factors known to drive worse COVID-19 outcomes include age, obesity, hypertension, and cardiac diseases.

The greater exposure children have to the common cold may also offer protection. Coronaviruses are a large family of viruses so named for their crown-like shape under a microscope, of which the common cold is one. SARS-CoV-2, which causes COVID-19, is another.

It is thought that exposure to colds may cause viral interference, when one virus interferes with the replication of a second virus. Exposure to common colds, and more severe illnesses like croup, more common in children, are associated with decreased expression of the ACE2 COVID-19 receptor. Studies have found that children symptomatic with COVID-19 may have high viral loads in their noses but, because they have lower levels of ACE2, their lungs are less likely to become infected. In other words, they can still easily spread the virus, but are less likely to develop serious symptoms.

Kaminski added that there is even evidence that vaccines can provide protection. Astudyof Department of Defense personnel found that the 2017-2018 seasonal flu vaccine produced a statistically significant number of individuals who tested positive for common cold-related coronaviruses. If future flu vaccines are designed to increase common coronaviruses, he said, this phenomenon may actually provide some protection to SARS-CoV-2 through cross-reactive immunity.

Of course, not all children are protected from the worst effects of COVID-19. Lucas and her team of pediatric immune disease researchers at Yale are looking at the rare cases of children who have been seriously affected by the virus. Specifically, they looked at children who were asymptomatic during SARS-CoV-2 infection, but weeks later developed a high fever, vomiting, abdominal pain, and sometimes shock, a condition known as MIS-C.As of Sept. 17, there were 935 confirmed cases of MIS-C in the U.S., and 19 deaths.

Lucas lab, which has enrolled 16 pediatric MIS-C patients, is analyzing immune cells in their blood at the single-cell level, as well as thousands of blood proteins, to understand what is happening.

Mostly, right now, our data are showing what the syndrome isnot, she said. For instance, we have found no sign of an active viral or bacterial infection during acute MIS-C.

They are also collecting saliva samples from parents to compare to childrens samples, which might reveal information about genetic variants. Were looking for the needle in the haystack that could be causing this rare manifestation, Lucas said. So far, theres no evidence that this is something that runs in families. I dont know of any cases where two children in a family developed MIS-C.

What they do know, she said, is that inflammatory markers are high, and most patients respond well to immunosuppressive therapies such as steroids. Additional findings will be published in the coming weeks on MedRxiv, a preprint server founded by Yale scientists which publishes studies before they have been peer-reviewed.

While children largely seem to be protected from the immediate effects of COVID-19, there are still long-term concerns, Kaminski and the authors caution. The pandemic and social distancing, they note, affect maturation of the immune system, psychological health, education, and childhood obesity.

We know that the health of children is strongly affected by socioeconomic downturns, Kaminski said, and this potential adverse outcome should not be overlooked.

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What we know about COVID-19 and kids - Yale News

(The Conversation is an independent and nonprofit source of news, analysis and commentary from academic experts.)

William Petri, University of Virginia

(THE CONVERSATION) With COVID-19 vaccines currently in the final phase of study, youve probably been wondering how the FDA will decide if a vaccine is safe and effective.

Based on the status of the Phase 3 trials currently underway, it is unlikely that the results of these trials will be available before November. But it is likely that not just one but several of the competing COVID-19 vaccines will be shown to be safe and effective by the end of 2020.

I am a scientist and infectious diseases specialist at the University of Virginia, where I care for patients with COVID-19 and conduct research on the pandemic. I am also a member of the World Health Organization Expert Group on COVID-19 Vaccine Prioritization.

What is the status of COVID-19 vaccines in human clinical trials?

Phase 3 studies are underway for the Moderna and BioNTech/Pfizer vaccines and the Oxford/AstraZeneca viral vector vaccine.

Each of these vaccines uses the SARS-CoV-2 spike glycoprotein, which the virus uses to infect cells, to trigger the immune system to generate protective antibodies and a cellular immune response to the virus. Protective antibodies act by preventing the spike glycoprotein from attaching the virus to human cells, thereby neutralizing the SARS-CoV-2 virus that causes COVID-19.

In the case of Modernas nucleic acid vaccine, the messenger RNA encoding the spike glycoprotein is encased in a fat droplet called a liposome to protect the mRNA from degradation and enable it to enter cells. Once these instructions are inside the cells, the mRNA is read by the human cell machinery and made into many spike proteins so that the immune system can respond and begin producing antibodies against this coronavirus.

The Oxford/AstraZeneca uses a different strategy to activate an immune response. Here an adenovirus found in chimpanzees shuttles the instructions for manufacturing the spike glycoprotein into cells.

Phase 1 and 2 studies by pharmaceutical companies Janssen and Merck also use viral vectors similar to the Oxford/AstraZeneca vaccine, while vaccines by Novavax and GSK-Sanofi use the actual spike protein itself.

Animal tests show the vaccines provide protection from coronavirus infection

Studies in animal models of COVID-19 provide convincing evidence that vaccination with the spike glycoprotein will protect from COVID-19. Experiments have show that when the immune system is shown the spike protein which alone cannot trigger disease the immune system will generate an antibody response that protects from infection with SARS-CoV-2.

In studies in hamsters an adenovirus viral vector the approach used by Oxford/AstraZeneca, for example was used to immunize with the Spike glycoprotein. When the hamsters were infected with SARS-CoV-2 they were protected from pneumonia, weight loss and death.

In nonhuman primates, DNA vaccines which deliver the gene for the spike glycoprotein reduced the amount of virus in the lungs. Animals that produced antibody that prevented virus attachment to human cells were most likely to be protected.

What have the early Phase 1 and 2 studies in humans shown?

Overall, vaccination has triggered a more potent neutralizing antibody response than even that seen in patients recovering from COVID-19.

This has also been the case for Modernas vaccine currently in Phase 3 trials and for vaccines from CanSino Biologics and Oxford/ AstraZeneca.

What side effects have been observed?

Physicians have recorded mild to moderate reactions when the subjects were observed up to 28 days after vaccination. These side effects included mild pain, warmth and tenderness at the site of injection, and fever, fatigue, joint and muscle pain.

But Phase 1 and 2 studies are by small by design, with just hundreds of participants. So these trials will not be large enough to detect uncommon or rare side effects.

The emphasis on safety as the primary goal was recently demonstrated in the Phase 3 Oxford/AstraZeneca vaccine trial where one vaccinated individual developed inflammation of the spinal cord. It isnt clear whether the vaccine caused this reaction it might be a new case of multiple sclerosis unrelated to the vaccine but the Phase 3 trial was halted in the U.S. until more is known.

How is the FDA ensuring that a vaccine will be safe yet quickly produced?

The FDA has issued guidance for industry on the steps required for developing and ultimately licensing vaccines to prevent COVID-19 these are the same rigorous safety standards required for all vaccines.

There are, however, ways to speed the process of approval that are centered on platform technology. What this means is that if a vaccine is using an approach such as an adenovirus that has previously been shown to be safe, it may be possible for a company to use previously collected data on toxicity and pharmacokinetics to fast-track clinical trial approval.

While speed and safety may appear conflicting goals, it is also encouraging to note that the rival vaccine manufacturers have jointly pledged not to bow to any political pressures to rush vaccine approval, but to maintain the most rigorous safety standards.

How protective does a vaccine need be to receive FDA approval?

The FDA has set the bar for the primary endpoint of a Phase 3 trial of 50% protection for approval of a COVID-19 vaccine.

Protection is defined as protection from symptomatic COVID-19 infection, defined as laboratory-confirmed SARS-CoV-2 infection plus symptoms such as fever or chills, cough, shortness of breath, fatigue, muscle aches, loss of taste or smell, congestion or runny nose, diarrhea, nausea or vomiting.

This means that an effective vaccine is considered one that will reduce the number of infections in vaccine recipients by half. This is the minimal protection that is anticipated to be clinically useful. That is, in part, because lower levels of efficacy could paradoxically increase COVID-19 infections if it leads vaccinated people to decrease mask wearing or social distancing because they think they are completely protected.

Since a vaccine might be more effective at preventing severe COVID-19, the FDA instructs that protection from severe COVID-19 should be a secondary endpoint.

How many people have to be vaccinated to know if a vaccine works in Phase 3?

The current Phase 3 trials are enrolling 30,000-40,000 subjects. Most of these participants will receive the vaccine and some a placebo.

When, exactly, the results of Phase 3 studies will be released depends in large part on the rate of infection in the placebo recipients. The way that these vaccine studies work is that they test if naturally acquired new coronavirus infections are lower in the group that received the vaccine compared with the group receiving the placebo.

So while it is good news that COVID-19 infections have dropped recently in the U.S. from 70,000 to 40,000 cases per day, this drop in new infections may slow the vaccine studies.

Will Emergency Use Authorization fast-track vaccine?

In an emergency such as we are faced with the COVID-19 pandemic, with approximately 700 new deaths and 40,000 new cases per day right now, the FDA is authorized to allow the use of unapproved products for the diagnosis, treatment and prevention of disease. That includes a vaccine.

The standard approval process for vaccines can require more than one year of observation after vaccination. If the short-term safety is good and the vaccine works to prevent COVID-19, then the vaccine should be approved for use under an Emergency Use Authorization while it is still being studied.

Under Emergency Use Authorization, the FDA will continue to collect information from the companies producing the vaccines for benefit and harm, including surveillance for vaccine-associated enhanced respiratory disease or other potentially rare complications that might be observed in only one in a million.

What should we expect in terms of approvals?

I expect that the FDA will approve several vaccines by the end of 2020 under its Emergency Use Authorization authority so that vaccination can begin immediately, starting with high-risk groups including first responders, health care personnel, and the elderly and those with preexisting medical conditions.

This will be followed rapidly with roll-out of vaccination to the population at large, while all of the time the FDA and vaccine manufacturers will continue to monitor for side effects and work to improve upon these first vaccines. This process is expected to take months.

It may not be life back to normal next year, but all signs point to a healthier 2021.

This article is republished from The Conversation under a Creative Commons license. Read the original article here: https://theconversation.com/how-and-when-will-we-know-that-a-covid-19-vaccine-is-safe-and-effective-146091.

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How and when will we know that a COVID-19 vaccine is safe and effective? - Fairfield Citizen

Findings from a new study demonstrated that infants exposed to opioids prior to birth had a two times higher odds of developing asthma.

The results underscore the necessity of maintaining close follow up care in this vulnerable patient population.

In the past 10 years, prenatal opioid exposure (POE) has seen a dramatic increase among the US newborn population. As many as 100 infants are born daily with Neonatal Opioid Withdrawal Syndrome (NOWS).Therefore, there lies a great need in investigating long-term outcomes in such patients.

Isabella Cervantes, BA, of the University of New Mexico School of Medicine, and colleagues designed a retrospective cohort study to determine the association between POE and the likelihood of an altered immune response by 8 years of age. Immune response was measured by the development of asthma.

To do this. Cervantes and team pulled data from a comprehensive CERNER HealthFacts U.S. national database, which captures de-identified, longitudinal health record data from 800 hospitals across the country.

The investigators used ICD-9-CM and ICD-10-CM diagnostic codes to identify infant patients born at term who had confirmed prenatal exposure to opioids or Neonatal Opioid Withdrawal Syndrome (NOWS).

Then they compared this population of patients with infants who had neither diagnoses at birth. Data was analyzed using IBM Statistical Package for Social Sciences, and Pearsons Chi-Square test analysis was conducted to determine any association between POE and asthma diagnosis.

Overall, the study included 3021 patient records between 2000-2016. A majority of the population was male (50.7%), with Caucasian (61%) being the most represented race/ethnicity.

The investigators also noted that a majority of patients had Medicaid insurance (41.9%) and were raised in urban communities (92.5%).

As many as 50.4% of patients presented with POEversus 49.6% who had no known exposure.

In their analysis, the investigators found that up to 66.3% of all asthma patients (n = 172) were prenatally exposed to opioids.

Thus, after controlling for race, gender demographics, and insurance type, they determined that the odds of developing asthma were two times higher for the prenatally exposed group (OR, 21; 95% CI, 1.4-3.0; P<.0001) than those who did not have POE.

They considered a major strength of the study to be the vastness of the national database. Therefore, the results could be consistent across different regions in the US.

A limitation, however, were the diagnostic codes used to identify their patient population of interest. For example, the codes used to identify infants with prenatal opioid exposure included other diagnoses such as Drug Withdrawal Syndrome in Newborn. Other confounding variables included smoking in the household, among others.

To address such limitations, they highlighted a need to undertake a longitudinal, prospective, multisite study for the future.

These emerging results suggest infants with POE may have altered immune reactivity that not only impacts the newborn period but persists into childhood, they wrote.

Future investigations should aim to characterize in greater detail the impact of POE on the immune system so that new follow-up strategies or effective interventions can be developed, they concluded.

The study, Increased Incidence of Asthma in Children with Prenatal Opioid Exposure, was published online in The Univeristy of New Mexico Digital Repository.

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Prenatal Opioid Exposure Associated with Development of Asthma in Children - MD Magazine

No matter what the season is tea is undeniably one of the best beverages. After water, tea is the worlds most consumed beverage. Drinking tea could actually ward off some very serious conditions, including cancer and obesity. It might sound inflated, but some surveys have stated that the world drinks about six billion cups of tea a day.

Tea contains antioxidants, improves heart health, facilitates weight loss etc. It keeps the body hydrated. There is a large variety of teas available in the market today and in the list below, we share the ones that can build and boost your immune system.

1. Masala Chai: India is a land of spices and has mastered the art of curing ailments and illnesses using unique combination of spices and herbs. There are several magical and abundantly available spices in India that strengthen the immune system. Masala Chai usually contains six condiments, namely cardamom, cinnamon, star anise, pepper, cloves and ginger. Their concoction will keep you pink of health.

2. Ginger Green Tea: A body is more susceptible to catch flue during changing seasons. This is that time of the year when one needs to take good care of their immune system and diet. Make ginger green tea your bae. Ginger, which is used extensively in Indian households, consists of anti-inflammatory components and antioxidants that can cure inflammation.

3. Cinnamon Green Tea: Cinnamon is a commonly used spice globally. It is derived from the inner bark of a small evergreen tree. Adding cinnamon stick or cinnamon powder to the tea enhances its potential. This magical ingredient is believed to reduce the risk of cardiovascular disease, improves digestion, and keeps a check on diabetes among other health benefits.

Inputs by Nutritionist Tripti Tandon

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Need better immunity? Try these teas! - Hindustan Times

The connection between the pandemic and our dietary habits is undeniable. The stress of isolation coupled with a struggling economy has caused many of us to seek comfort with our old friends: Big Mac, Tom Collins, Ben and Jerry. But overindulging in this kind of food and drink might not just be affecting your waistline, but could potentially put you at greater risk of illness by hindering your immune system.

Hear the word nutrition, and often what comes to mind are fad diets, juice cleanses and supplements. Americans certainly seem concerned with their weight; 45 million of us spend US$33 billion annually on weight loss products. But one in five Americans consumes nearly no vegetables less than one serving per day.

When the emphasis is on weight loss products, and not healthy day-to-day eating, the essential role that nutrition plays in keeping us well never gets communicated. Among the many things I teach students in my nutritional biochemistry course is the clear relationship between a balanced diet and a strong, well-regulated immune system.

Along with social distancing measures and effective vaccines, a healthy immune system is our best defense against coronavirus infection. To keep it that way, proper nutrition is an absolute must. Although not a replacement for medicine, good nutrition can work synergistically with medicine to improve vaccine effectiveness, reduce the prevalence of chronic disease and lower the burden on the health care system.

Scientists know that people with preexisting health conditions are at greater risk for severe COVID-19 infections. That includes those with diabetes, obesity, and kidney, lung or cardiovascular disease. Many of these conditions are linked to a dysfunctional immune system.

Patients with cardiovascular or metabolic disease have a delayed immune response, giving viral invaders a head start. When that happens, the body reacts with a more intense inflammatory response, and healthy tissues are damaged along with the virus. Its not yet clear how much this damage factors into the increased mortality rate, but it is a factor.

What does this have to do with nutrition? The Western diet typically has a high proportion of red meat, saturated fat and whats known as bliss point foods rich in sugar and salt. Adequate fruit and vegetable consumption is missing. Despite the abundance of calories that often accompanies the Western diet, many Americans dont consume nearly enough of the essential nutrients our bodies need to function properly, including vitamins A, C and D, and the minerals iron and potassium. And that, at least in part, causes a dysfunctional immune system: too few vitamins and minerals, and too many empty calories.

A healthy immune system responds quickly to limit or prevent infection, but it also promptly turns down the dial to avoid damaging the cells of the body. Sugar disrupts this balance. A high proportion of refined sugar in the diet can cause chronic, low-grade inflammation in addition to diabetes and obesity. Essentially, that dial is never turned all the way off.

While inflammation is a natural part of the immune response, it can be harmful when its constantly active. Indeed, obesity is itself characterized by chronic, low-grade inflammation and a dysregulated immune response.

And research showsthat vaccines may be less effective in obese people. The same applies to those who regularly drink too much alcohol.

Nutrients, essential substances that help us grow properly and remain healthy, help maintain the immune system. In contrast to the delayed responses associated with malnutrition, vitamin A fights against multiple infectious diseases, including measles. Along with vitamin D, it regulates the immune system and helps to prevent its overactivation. Vitamin C, an antioxidant, protects us from the injury caused by free radicals.

Polyphenols, a wide-ranging group of molecules found in all plants, also have anti-inflammatory properties. Theres plenty of evidence to show a diet rich in plant polyphenols can lower the risk of chronic conditions, like hypertension, insulin insensitivity and cardiovascular disease.

Why dont we Americans eat more of these plant-based foods and fewer of the bliss-based foods? Its complicated. People are swayed by advertising and influenced by hectic schedules. One starting place would be to teach people how to eat better from an early age. Nutrition education should be emphasized, from kindergarten through high school to medical schools.

Millions of Americans live in food deserts, having limited access to healthy foods. In these circumstances, education must be paired with increased access. These long-term goals could bring profound returns with a relatively small investment.

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Meantime, all of us can take small steps to incrementally improve our own dietary habits. Im not suggesting we stop eating cake, french fries and soda completely. But we as a society have yet to realize the food that actually makes us feel good and healthy is not comfort food.

The COVID-19 pandemic wont be the last we face, so its vital that we use every preventive tool we as a society have. Think of good nutrition as a seat belt for your health; it doesnt guarantee you wont get sick, but it helps to ensure the best outcomes.

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Good nutrition can contribute to keeping COVID-19 and other diseases away - The Conversation US

With COVID-19 vaccines currently in the final phase of study, youve probably been wondering how the Food and Drug Administration will decide if a vaccine is safe and effective.

Based on the status of thePhase 3 trialscurrently under way, it is unlikely that the results of these trials will be available before November. But it is likely that not just one but several of the competing COVID-19 vaccines will be shown to be safe and effective by the end of 2020.

I am a scientist and infectious diseases specialistat the University of Virginia, where I care for patients with COVID-19 and conduct research on the pandemic. I am also a member of the World Health Organization Expert Group on COVID-19 Vaccine Prioritization.

Phase 3 studies are under wayfor the Moderna MRNA, -0.78% and BioNTech BNTX, +1.40% /Pfizer PFE, +0.63% vaccines and the Oxford/AstraZeneca AZN, -0.37% AZN, -0.84% viral vector vaccine.

Follow the latest news on the coronavirus on MarketWatch

Each of these vaccines uses the SARS-CoV-2 spike glycoprotein, which the virus uses to infect cells, to trigger the immune system to generate protective antibodies and a cellular immune response to the virus. Protective antibodies act by preventing the spike glycoprotein from attaching the virus to human cells, thereby neutralizing the SARS-CoV-2 virus that causes COVID-19.

In the case ofModernas nucleic acid vaccine, the messenger RNA encoding the spike glycoprotein is encased in a fat dropletcalled a liposometo protect the mRNA from degradation and enable it to enter cells. Once these instructions are inside the cells, the mRNA is read by the human cell machinery and made into many spike proteins so that the immune system can respond and begin producing antibodies against this coronavirus.

The Oxford/AstraZeneca uses a different strategy to activate an immune response. Here an adenovirus found in chimpanzees shuttles the instructions for manufacturing the spike glycoprotein into cells.

Phase 1 and 2 studies by the pharmaceutical companies Janssen and Merck MRK, -0.22% also use viral vectors similar to the Oxford/AstraZeneca vaccine, while vaccines by Novavax NVAX, +1.34% and GSK GSK, -0.55% and Sanofi SNY, -1.94% use the actual spike protein itself.

Studies in animal models of COVID-19 provide convincing evidence that vaccination with the spike glycoprotein will protect from COVID-19. Experiments have show that when the immune system is shown the spike proteinwhich alone cannot trigger diseasethe immune system will generate an antibody response that protects from infection with SARS-CoV-2.

In studies in hamstersan adenovirus viral vectorthe approach used by Oxford/AstraZeneca, for examplewas used to immunize with the spike glycoprotein. When the hamsters were infected with SARS-CoV-2 they were protected from pneumonia, weight loss and death.

In nonhuman primates, DNA vaccineswhich deliver the gene for the spike glycoproteinreduced the amount of virus in the lungs. Animals that produced an antibody that prevented virus attachment to human cells were most likely to be protected.

Overall,vaccination has triggered a more potent neutralizing antibody responsethan even that seen in patients recovering from COVID-19.

This has also been the case forModernas vaccine currently in Phase 3 trialsand for vaccines fromCanSino Biologics 6185, -1.24% and Oxford/ AstraZeneca.

Physicians have recordedmild to moderate reactionswhen the subjects were observedup to 28 days after vaccination. These side effects included mild pain, warmth and tenderness at the site of injection, and fever, fatigue, joint and muscle pain.

But Phase 1 and 2 studies are by small by design, with just hundreds of participants. So these trials will not be large enough to detect uncommon or rare side effects.

The emphasis on safety as the primary goal was recently demonstrated in the Phase 3 Oxford/AstraZeneca vaccine trialwhere one vaccinated individual developed inflammation of the spinal cord. It isnt clear whether the vaccine caused this reactionit might be a new case of multiple sclerosis unrelated to the vaccinebut the Phase 3 trial was halted in the U.S. until more is known.

TheFDA has issued guidance for industryon the steps required for developing and ultimately licensing vaccines to prevent COVID-19these are the same rigorous safety standards required for all vaccines.

There are, however, ways to speed the process of approval that are centered on platform technology.

What this means is that if a vaccine is using an approach such as an adenovirus that has previously been shown to be safe, it may be possible for a company to use previously collected data on toxicity and pharmacokinetics to fast-track clinical trial approval.

ile speed and safety may appear conflicting goals, it is also encouraging to note that therival vaccine manufacturers have jointly pledgednot to bow to any political pressures to rush vaccine approval, but to maintain the most rigorous safety standards.

The FDA has set the bar for the primary endpoint of a Phase 3 trial of 50% protection for approval of a COVID-19 vaccine.

Protection is defined as protection from symptomatic COVID-19 infection, defined as laboratory-confirmed SARS-CoV-2 infection plus symptoms such as fever or chills, cough, shortness of breath, fatigue, muscle aches, loss of taste or smell, congestion or runny nose, diarrhea, nausea or vomiting.

This means that an effective vaccine is considered one that will reduce the number of infections in vaccine recipients by half. This is theminimal protection that is anticipated to be clinically useful. That is, in part, because lower levels of efficacy could paradoxically increase COVID-19 infections if it leads vaccinated people to decrease mask wearing or social distancing because they think they are completely protected.

Since a vaccine might be more effective at preventing severe COVID-19, the FDA instructs thatprotection from severe COVID-19should be a secondary endpoint.

FDA to announce tough guidelines that could delay approval of vaccine, Washington Post reports

The current Phase 3 trials are enrolling 30,000-40,000 subjects. Most of these participants will receive the vaccine and some a placebo.

When, exactly, the results of Phase 3 studies will be released depends in large part on the rate of infection in the placebo recipients. The way that these vaccine studies work is that they test if naturally acquired new coronavirus infections are lower in the group that received the vaccine compared with the group receiving the placebo.

So while it is good news that COVID-19 infections have dropped recently in the U.S. from70,000 to 40,000 cases per day, this drop in new infections may slow the vaccine studies.

In an emergency such as we are faced with the COVID-19 pandemic, with approximately 700 new deaths and 40,000 new cases per day right now, the FDA is authorized to allow the use of unapproved products for the diagnosis, treatment and prevention of disease. That includes a vaccine.

The standard approval process for vaccinescan require more than one year of observation after vaccination. If the short-term safety is good and the vaccine works to prevent COVID-19, then the vaccine should be approved for use under an Emergency Use Authorization while it is still being studied.

Under Emergency Use Authorization, the FDA willcontinue to collect informationfrom the companies producing the vaccines for benefit and harm, including surveillance for vaccine-associated enhanced respiratory disease or other potentially rare complications that might be observed in only one in a million.

I expect that the FDA will approve several vaccines by the end of 2020 under its Emergency Use Authorization authority so that vaccination can begin immediately, starting with high-risk groups including first responders, health-care personnel, and the elderly and those with pre-existing medical conditions.

This will be followed rapidly withrollout of vaccinationto the population at large, while all of the time the FDA and vaccine manufacturers will continue to monitor for side effects and work to improve upon these first vaccines. This process isexpected to take months.

It may not be life back to normal next year, but all signs point to a healthier 2021.

William Petri is professor of medicine at the University of Virginia.

This commentary was originally published by The ConversationHow and when will we know that aCOVID-19vaccine is safe andeffective?

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Abstract

COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1 and IP-10, and most strikingly, modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, as well as enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of COVID-19 patients and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission suggesting immune-modulating therapies would be most beneficial at early timepoints.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in the clinical syndrome COVID-19 (1) that, to date, has resulted in over 20 million confirmed cases and in excess of 733,000 attributable deaths world-wide. As such, a large number of clinical trials have been established to evaluate anti-viral and immune modulatory strategies aimed at improving clinical outcome for this globally-devastating virus.

SARS-CoV-2 is a single stranded, positive sense RNA virus that enters cells via human angiotensin-converting enzyme 2 (ACE2) (2). Ordinarily, diverse immune mechanisms exist to detect every stage of viral replication and protect the host from viral challenge. Pattern recognition receptors of the innate immune system recognize viral antigen and virus-induced damage, increasing bone marrow hematopoiesis, the release of myeloid cells including neutrophils and monocytes, and the production of a plethora of cytokines and chemokines (3). If inflammatory mediator release is not controlled in duration and amplitude then emergency haematopoiesis leads to bystander tissue damage and a cytokine storm that manifests as organ dysfunction. Initial studies suggest cytokine storm occurs in COVID-19 (4). Indeed, neutrophilia and lymphopenia (resulting in an increased neutrophil to lymphocyte ratio), increased systemic interleukin-6 (IL-6) and C-reactive protein (CRP), correlate with incidence of intensive care admission and mortality (5). However, detailed understanding of cellular and molecular inflammatory mediators across the COVID-19 disease trajectory would support the development of better clinical interventions.

We carried out the Coronavirus Immune Response and Clinical Outcomes (CIRCO) study at four hospitals in Greater Manchester, UK, which was designed to examine the kinetics of the immune response in COVID-19 patients, as well as to identify early indicators of disease severity. Understanding the specific elements and kinetics of the immune response is critical to gain insight into immune phenotypes associated with disease progression, identify potential biomarkers that predict clinical outcomes and determine at which stage of the disease immune modulation may be most effective (4).

Here, by analyzing fresh blood samples immediately without prior storage we outline unappreciated immune abnormalities present within COVID-19 patients. Assessment of inflammatory mediators within the blood demonstrated these immune properties were most dysregulated in patients with severe COVID-19 prior to admission to intensive care, indicating immune modulating therapies should be considered early after admission. Furthermore, our study demonstrated profound alterations in the myeloid cells of COVID-19 patients. Our data demonstrate that monocytes from COVID-19 patients displayed elevated levels of the cell cycle marker Ki-67 but reduced expression of the prostaglandin-generating enzyme COX-2, with both these features being predominant in severe COVID-19 patients. These findings not only identify possible immune biomarkers for patient stratification but potential mechanisms of immune dysfunction contributing to the immunopathology of COVID-19.

In total, 73 patients were recruited and 49 were stratified for maximum disease severity (Fig. 1A). Six patients were excluded due to: an alternative diagnosis (2 patients); indeterminate imaging findings with negative result in the SARS-CoV-2 nasopharyngeal test (2 patients); or diagnosis of a confounding acute illness (2 patients). Two patients could not be stratified for disease severity due to insufficient clinical observation data and a further 16 were not stratified because recruitment occurred more than 7 days after admission. The median time from patient-reported symptom onset to hospital admission was 7 days. The overall median age was 61 and 63% were male. The most frequent co-morbidities were diabetes, ischemic heart disease, hypertension, asthma and chronic obstructive pulmonary disease (COPD) (Table 1). The majority (86%) of patients tested positive for SARS-CoV-2 via nasopharyngeal RT-PCR. In 14% of patients, symptoms and radiographic features were highly suggestive of COVID-19, but nasopharyngeal test was negative for the virus and thus a clinical diagnosis was made; these patients are clearly indicated in all graphs (white triangles). Patient disease severity was defined as mild (less than 28% FiO2), moderate (28-60% FiO2) or severe (above 60% FiO2, or admission to intensive care) (Fig. 1B). Death occurred in 50% of severe cases of COVID-19 and only one of the ten patients with severe disease was categorized as severe upon admission.

Patient recruitment and categorization. (A) Patients were recruited to the study as close to admission as possible and within 7 days. Peripheral blood samples were collected on recruitment and at intervals thereafter. Samples were analyzed immediately and results stratified based on their ultimate disease severity. (B) Criteria for patient stratification. NIV, non-invasive ventilation; CPAP, continuous positive airway pressure; ICU, intensive care unit.

Data are listed as median (IQR) m, where m is the number of missing data points, n (%), or n/N (%), where N is the total number with available data. PE, pulmonary embolism; AKI, Acute kidney injury. aAdmission observations. Representative participants from each severity cohort were used in cross-sectional or longitudinal analysis.

Based on blood cell counts by the hospital laboratory at admission, no significant differences in total white blood cells, neutrophils, monocytes or lymphocytes were observed between groups of COVID-19 patients that went on to progress to mild, moderate or severe disease (Fig. S1A). However, as reported previously (6, 7), a trend was evident toward a higher neutrophil to lymphocyte ratio (NLR) at hospital admission in those patients whose outcome eventually was severe (Fig. S1B). This suggested that a more in-depth immune profiling could aid in patient stratification prior to escalation of the disease.

Thus, we further explored alterations in the innate and adaptive immune compartments using high dimensional flow cytometry on white blood cells from freshly lysed whole blood (see Fig. S1C for gating strategy). Initially, we examined the first blood sample taken at the time of patient recruitment to the study (this was typically 2-3 days after hospital admission and was not greater than 7 days). At this recruitment time point, alterations to the characteristics and relative abundance of diverse immune cell types was observed. Uniform manifold approximation and projection (UMAP) visualization outlined alterations between patients and healthy controls in the characteristics of neutrophils and monocytes, dramatic increases in the frequency of neutrophils and decreased T cells, B cells and basophils. Cellular changes were exaggerated with disease severity (Fig. 2A). In a subset of infected individuals CD16low granulocytes were present (Fig. 2A); these cells can be associated with altered immune cell output from the bone marrow (8). This global picture of alterations to innate and adaptive immune cells was confirmed by manual flow cytometric gating (Fig. 2B and Fig. S1, C and D). In addition to these alterations, examining cell frequencies within isolated peripheral blood mononuclear cells (PBMCs) revealed a decrease in the frequency of plasmacytoid dendritic cells (pDCs) in COVID-19 patients, that was enhanced with elevated disease severity (Fig. S1E). There were no changes observed in frequencies of CD56+ NK cells (Fig. S1E).

Whole blood immune profile of COVID-19 patients. (A) Uniform Manifold Approximation and Projection (UMAP) of flow cytometry panel broadly visualizing white cells in whole blood. Representative images for healthy individuals, mild, moderate and severe patients are shown. Key indicates cells identified on the image. (B) Graphs show neutrophil (CD16+CD11bhi), CD14+ monocyte, CD3+ T cell, and CD19+ B cell frequencies in whole blood samples of healthy individuals (n=28) and recruitment samples from COVID-19 patients with mild (n=12), moderate (n=13) and severe (n=6) disease. (C) Longitudinal time course of (top row) neutrophils (CD16+CD11bhi), (2nd row) CD14+ monocytes, (3rd row) CD3+ T cells and (bottom row) B cells segregated by disease severity. Individual patients are shown as different colors and shapes with lines connecting data from the same patient. Crossed squares for severe patients are time points in intensive care unit (ICU). X axis values represent the number of days since reported onset of symptoms. (D) Graphs showing frequencies of neutrophils (CD16+CD11bhi), monocytes, T cells and B cells at the first and last time points in (left) mild/moderate patients (green and blue circles) and (right) severe patients (black circles). Red triangles represent severe patients that had poor outcome (deceased or long-term ICU) and are not included in the statistical test. Graphs show individual patient data with the bar representing median values. In all graphs, open triangles represent SARS-CoV-2 PCR negative patients. Kruskal Wallis with Dunns post-hoc test; 2B Neutrophils, T cells and B cells. One-way ANOVA with Holm-Sidak post-hoc test: 2B Monocytes. Paired t-test; 2D all except monocyte graph detailing mild and moderate patients which was tested using Wilcoxon matched-pairs signed rank test. (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001).

Given the dramatic alterations in neutrophil and T cell frequencies at the time of recruitment (Fig. 2B), we next examined their profile longitudinally over the course of hospitalization. To do this we used the first day of patient-reported symptom onset as a common reference point to align patient disease trajectories. This revealed that in the majority of patients, irrespective of final severity, neutrophil frequencies, although initially extremely high, decreased prior to hospital discharge while T cell frequencies reciprocally increased (Fig. 2C and 2D). In contrast, CD14+ monocytes and B cells showed no obvious trends during the hospital stay (Fig. 2C and D). These data highlight the importance of examining neutrophil to lymphocyte ratio in COVID-19 patients (6, 7), but, along with other studies (9), indicate that assessment of neutrophil to T cell ratio may provide a more stringent disease insight. Notably, in two severe patients with poor outcome, T cell frequencies were extremely low and neutrophil frequencies high even after entry into an intensive care unit (ICU) (Fig. 2C; white and pink crossed squares and Fig. 2D, red triangles); indicating that rebalancing of neutrophil to T cell ratio is crucial to recovery.

Broad changes in circulating immune cells in other viral infections are associated with alterations to circulating inflammatory mediators, such as cytokines and chemokines. These are potent modifiers of bone marrow output, immune cell survival and cell-recruitment to the inflamed lung. We used multiplex bead array to assess soluble inflammatory mediators in serum from patients at recruitment to the study. Of the 13 mediators analyzed in serum IL-6, IL-10, monocyte-chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein 10 (IP-10) were significantly increased in COVID-19 patients and tracked with disease severity (Fig. S2A). No significant changes in other cytokines or chemokines measured, including IFN-, IL-1, IL-8 and TNF- were observed in COVID-19 patients (Fig. S2B).

Interestingly, longitudinal analysis (examined as above from the day of reported disease onset) of IL-6, MCP-1 and IP-10 in mild and severe patients revealed that the highest levels of these cytokines and chemokines occurred early in the disease trajectory at recruitment to the study (Fig. S2C). Indeed, there was a significant decrease in IL-6 and IP-10 in patients upon recovery (Fig. S2D). There was a dramatic reduction in IL-6, IP-10 and MCP-1 upon admission of severe patients into ICU from the ward (Fig. S2E), although this finding is based on just 3 patients. This may be due to the treatment modalities employed in intensive care, such as sedation, that can have immunomodulatory effects (10), and will be important to investigate further. Interestingly, the patient whose health declined rapidly following admission, and ultimately died from the disease, displayed a dramatic rebound in IL-6 and MCP-1 levels after 2 days on ICU (Fig. S2, D and E; red triangles).

To build on our basic assessment of cell populations outlined in Fig. 2, we next investigated alterations to specific T and B cell populations by flow cytometrically analyzing isolated peripheral blood mononuclear cells (PBMCs). Within the T cell compartment, we noted no dramatic alterations in CD4+ or CD8+ T cell frequencies (Fig. 3A and B). However, a slight decrease in CD4+ T cells was observed in severe COVID-19 patients (Fig. 3B). Both T cell subsets showed signs of activation in COVID-19 patients and this was more apparent in CD8+ T cells. Of note, the degree of T cell activation did not track with disease severity and was highly variable amongst patients (Fig. S3, A to D). Despite this, COVID-19 patients exhibited decreased frequencies of naive but elevated frequencies of effector TEMRA and HLA-DR+CD38+ CD8+ T cells (Fig. S3, A to C). CD8+ T cell subsets remained remarkably stable over the hospitalized disease course (Fig. S3E).

Altered phenotype of T and B cells in COVID-19 patients. (A,B) Graphs show frequencies of (A) CD8+ and (B) CD4+ T cells in freshly isolated PBMCs of healthy individuals (n=36) and recruitment samples from COVID-19 patients with mild (n=17), moderate (n=18) and severe (n=9-10) disease. (C,D) Representative flow cytometry plots and graph showing frequency of CD8+ T cells which are positive for perforin in healthy individuals (n=21 and COVID-19 patients with mild (n=16), moderate (n=12) and severe (n=7) disease. (E) Graph showing correlation of perforin+ CD8+ T cell frequency with C-reactive protein (CRP) in COVID-19 patients. (F) Graphs show frequencies of CD19+ B cells in freshly isolated PBMCs of healthy individuals (n=43) and recruitment samples from COVID-19 patients with mild (n=14), moderate (n=19) and severe (n=9) disease. (G) Representative flow cytometry plots and cumulative data show Ki-67 expression by B cells in healthy individuals (n=39) and COVID-19 patients (n=45). Correlation graph shows correlation of Ki-67+ B cells with C-reactive protein (CRP). (H) Representative flow cytometry plots and cumulative data show frequency of CD27hiCD38hi plasmablasts in healthy individuals (n=42) and COVID-19 patients (n=66). (I) Correlation graph shows correlation of plasmablasts and IgG+ B cell frequencies. (J) Graph shows frequencies of double negative (CD27-IgD-) B cells in freshly prepared PBMC of healthy individuals (n=42) and recruitment samples from COVID-19 patients with mild (n=14), moderate (n=19) and severe (n=9) disease. Graphs show individual patient data with the bar representing median values. In all graphs, open triangles represent SARS-CoV-2 PCR negative patients. Mann-Whitney U test; 3G, 3H. Kruskal Wallis with Dunns post-hoc test; 3A, 3D, 3F, 3J. One-way ANOVA with Holm-Sidak post-hoc test: 3B. Spearman ranked coefficient correlation test; 3E, 3G, 3I. (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001).

Interestingly, in 34/43 COVID-19 patients, higher perforin expression was observed in CD8+ T cells compared to healthy individuals (Fig. 3C and Fig. S3F), implying CD8+ T cells in COVID-19 patients had activated a cytotoxic program. Perforin expression in CD8+ T cells did not significantly track with disease severity (Fig. 3D), but a positive correlation was observed between the frequency of perforin+CD8+ T cells and clinical measurements of the inflammatory marker C-reactive protein (CRP) (Fig. 3E). This indicates increased frequencies of circulating perforin+ CD8+ T cells are more prevalent in highly inflamed patients. However, perforin+CD8+ T cells were found to increase over time in mild and most moderate COVID-19 patients, with highest levels immediately prior to discharge (Fig. S3, G to H), suggesting the higher frequencies seen in severe patients are not necessarily detrimental. This enhancement over time in mild and moderate patients suggests the higher frequencies seen in severe patients are not necessarily detrimental. Overall, these data demonstrate heterogeneous T cell activation in COVID-19 patients, but a consistent cytotoxic profile in the CD8+ T cell compartment.

Similar to the trend in whole blood (Fig. 2B), B cell frequency was reduced in PBMCs of COVID-19 patients. Decreases were particularly striking in severe patients compared to those with mild and moderate disease (Fig. 3F) and persisted with time (Fig. S4A). Although reduced in frequency, B cells displayed increased expression of Ki-67 (indicative of proliferation), which positively correlated with CRP levels (Fig. 3G). When examining B cell subsets, we observed an expansion of antibody-secreting plasmablasts (CD27hiCD38hiCD24), that positively correlated with IgG expression by B cells (Fig. 3H and I). Further, we observed a decrease in unswitched memory (CD27+IgD+IgM+) B cells but no global differences in frequencies of other B cell subsets (Fig. S4B). Of note, the differences in B cell subsets did not track with disease severity (Fig. S4C). The only subpopulation of B cells dramatically expanded in patients with severe COVID-19, compared to patients with mild and moderate disease, was double negative (DN) B cells (CD27IgD) (Fig. 3J). This subset was relatively stable throughout patient hospitalization and associated with a worse disease trajectory (Fig. S4D). DN B cells have previously been associated with an exhausted phenotype in patients with HIV (11), suggesting that patients with severe COVID-19 may have an impaired capacity to generate an effective B cell response.

COVID-19 research to date has primarily focused on T and B cells, although recent publications have highlighted alterations to monocyte phenotype (12). Monocytes can contribute significantly to inflammatory disease directly or via differentiation to macrophages and dendritic cells (13, 14). When released into the blood stream, monocytes will be affected by circulating cytokines and chemokines, including MCP-1, which we define as raised early in COVID-19 sera (Fig. S2A). In COVID-19 patients, we observed an expansion of intermediate CD14+CD16+ monocytes that tended to be highest in patients with a mild disease outcome (Fig. S5, A and B). Enhanced expression of CD64, the high affinity Fc receptor for monomeric IgG (FcRI), was apparent on classical CD14+ monocytes (Fig. 4A) and again was most evident in mild disease.

Dysregulation of circulating monocytes in COVID-19. (A) Graphs show levels of CD64 expression as assessed by mean fluorescence intensity (MFI) on CD14+ classical monocytes in freshly prepared PBMC of healthy individuals (n=25) and recruitment samples from all COVID-19 patients (n=58). COVID-19 patients were also stratified into mild (n=12), moderate (n=10) and severe (n=8) disease. (B) Graphs show frequencies of TNF-+ CD14+ monocytes following LPS stimulation of freshly prepared PBMC from healthy individuals (n=41) and COVID-19 patients (n=59). COVID-19 patients were also stratified into mild (n=14), moderate (n=15) and severe (n=7) disease. (C) Representative FACS plots demonstrating intracellular COX2 expression by CD14+ monocytes from healthy individuals and COVID-19 patients. (D, E) Graphs showing (D) frequencies of COX-2+ CD14+ monocytes and (E) COX-2 expression level as determined by MFI in CD14+ monocytes following LPS stimulation of freshly prepared PBMC from healthy individuals (n=33) and total COVID-19 patients (n=51). COVID-19 patients were also stratified into mild (n=12), moderate (n=11) and severe (n=6) disease. (F) Representative FACS plots demonstrating intracellular Ki-67 staining by CD14+ monocytes. (G) Graphs show frequencies of Ki-67+ CD14+ monocytes following LPS stimulation of freshly prepared PBMC from healthy individuals (n=37) and total COVID-19 patients (n=60). COVID-19 patients were also stratified into mild (n=14), moderate (n=14) and severe (n=8) disease. (H) Correlation of Ki-67 (% of monocytes expressing Ki-67) with CRP in COVID-19 patients. (I-K) Longitudinal time course of frequencies of CD14+ monocytes that are positive for (I) TNF-, (J) COX2 and (K) Ki-67 following LPS stimulation in mild (green shapes, n=6-7) and severe (black shapes, n=4-6) COVID-19 patients with lines connecting data from the same patient. On all graphs x axis values represent the number of days since onset of symptoms and the dotted line represents the median value from healthy individuals. (L) Graphs showing frequencies of monocytes which are TNF-+, COX-2 and Ki-67+ following LPS stimulation at the first and last time points in (left) mild patients (green circles) and (right) severe patients (black circles). Graphs show individual patient data with the bar representing median values. In all graphs, open triangles represent SARS-CoV-2 PCR negative patients. Mann-Whitney U test; 4A, 4B. 4D, 4E, 4G. Kruskal Wallis with Dunns post-hoc test; 4B, 4D, 4E, 4G. One-way ANOVA with Holm-Sidak post-hoc test:.4A. Spearman ranked coefficient correlation test; 4H. Paired t-test; 4L. (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001).

We next examined monocyte activation by stimulating with lipopolysaccharide (LPS); stimulation frequencies of viable cells were high (greater than 90%) and similar in COVID-19 patients and healthy controls. Following stratification for final disease severity, TNF- was enhanced in patients with mild disease (Fig. 4B and Fig. S5C). In contrast, IL-1 production was lower in monocytes from COVID-19 patients compared to monocytes from healthy individuals (Fig. S5D), although this was not related to disease severity. These data highlight that monocytes from COVID-19 patients exhibit a modified cytokine profile upon activation. As well as cytokines, monocytes are major producers of lipid mediators, such as prostaglandins (15) and so we also examined cyclooxygenase-2 (COX-2) expression (a rate-limiting enzyme in prostaglandin synthesis). Notably, in LPS-stimulated monocytes a reduction in COX-2 was evident in all COVID-19 patients and was most apparent in those with severe disease (Fig. 4, C to E). Accordingly, expression of COX-2 in stimulated monocytes was inversely correlated to systemic levels of the cytokine MCP-1 (Fig. S5E), which were highest in severe COVID-19 patients (Fig. S2A).

One possible reason that monocytes in COVID-19 patients display altered functionality in the periphery is due to inflammation-induced emergency myelopoiesis (3). This process occurs during infection where hematopoietic stem cells and myeloid progenitors expand in the bone marrow in order to provide more cells to combat viral infection. However, if egress is too fast then monocytes exit in an altered state. For example, unusually high expression of the cell cycle marker Ki-67 is observed in peripheral monocytes during H1N1 influenza (16) and Ebola virus (17) infection. We therefore, investigated expression of the proliferation marker Ki-67 in COVID-19. A striking increase in Ki-67+ monocytes (<5% in monocytes from most healthy controls) was evident in COVID-19 patients, but was most dramatic in patients with severe disease (Fig. 4, F and G). Ki-67 expression strongly correlated with CRP levels (Fig. 4H), and with systemic levels of the cytokines IL-6, MCP-1, IP-10 and IL-10 (Fig. S5F), cytokines that were enhanced in COVID-19 patients and tracked with severity (Fig. S2A). Enhancement of Ki-67 expression was also observed in unstimulated monocytes from COVID-19 patients (Fig. S5G).

We next assessed how monocyte alterations varied over the patients hospital stay and noted that patients with mild COVID-19 had consistently higher TNF- and COX-2 expression in LPS-activated monocytes compared to patients with severe disease (Fig. 4, I and J). Indeed, COX-2 remained low in severe patients throughout intensive care but levels were restored upon recovery in mild patients (Fig. 4L). IL-1 was consistently low over time in both severity groups with no significant differences in monocyte production of IL-1 between the first and last measured time points from mild or severe patients (Fig. S5H). Ki-67 expression, however, was highest at recruitment and decreased in patients (back down to levels seen in healthy controls) during the progression of disease, independent of severity category or final outcome (Fig. 4, K and L). Thus, defined alterations to monocyte function, specifically to TNF- and COX-2, are maintained across the disease time-course and levels of expression are associated with severity. Taken together, these findings highlight alterations to monocyte phenotype and function as key features of disease progression and severity in COVID-19.

Respiratory viruses continue to cause devastating global disease. This detailed, prospective, observational analysis of COVID-19 patients of varying severity and outcome, in real time, has revealed specific immunological features that track with disease severity, providing important information concerning pathogenesis that should influence clinical trials and therapeutics. Of particular importance, increased expression of the cell cycle marker Ki-67 in blood monocytes, reduced expression of COX-2, and a high neutrophil to T cell ratio are early predictors of disease severity that could be used to stratify patients upon admission for therapeutics. Critically, the majority of aberrant immune parameters studied reverted in patients with good outcome. Unexpectedly, multiple aspects of inflammation that were high upon admission, diminished as patients progressed in severity and were admitted to intensive care. In particular, levels of IP-10 and Ki-67 expression by monocytes were reduced after admission to intensive care, even in patients who did not recover. These data indicate that treating patients early after hospitalization is likely to be most beneficial, while cytokine levels and immune functions are disrupted.

Though other studies have focused on defects in adaptive immunity in COVID-19 pathogenesis (18), we demonstrate here considerable abnormalities in the innate immune system, in particular within myeloid cells. Profound neutrophilia exists in severe COVID-19, supportive of a role for neutrophils in acute respiratory distress syndrome (19, 20) and in line with the excess neutrophils seen in the autopsied lungs of patients that died from COVID-19 (21). Neutrophils assist in the clearance of pathogens through phagocytosis, oxidative burst and by liberating traps (neutrophil extracellular traps or NETs) that capture pathogens. The latter two functions, however, can also promote inflammation and are associated with many of the features seen in COVID-19 (22). Indeed, elevated neutrophil products have been identified in the sera of COVID-19 patients and correlate with clinical parameters such as C-reactive protein, D-dimer, and lactate dehydrogenase (23).

Altered monocyte phenotypes were also seen in COVID-19 patients, with patient blood monocytes expressing the cell cycle marker Ki-67 (up to 98%); a feature not observed in health. This likely represents either early or enhanced release of monocytes from the bone marrow due to systemic inflammatory signals and is similar to that described in pandemic H1N1 influenza (16) and Ebola virus infections (17). Equally remarkable was the reduced expression of COX-2 in monocytes in patients with severe disease, which was evident across their disease trajectory. COX-2 facilitates the production of prostanoids including prostaglandin E2 (PGE2), and other viruses are known to target this pathway to enhance viral replication (24). However, its reduction in monocytes in response to viral lung infection has not previously been reported. Reduced COX-2 alongside high IL-6 and IP-10, as seen here in severe COVID-19 patients, is an immune profile associated with pathology in idiopathic pulmonary fibrosis (IPF) (25). Therefore, our data indicate a possible fibrotic signature in patients with severe disease, supporting studies observing an unusual pattern of fibrosis in the lungs of COVID-19 patients.

Our data concur with several features of COVID-19 studied in Wuhan, China, as well as with more recent studies from across the globe (26, 27) and are also corroborated by single cell RNA sequencing of bronchoalveolar lavage cells at a single time point (28). Similarities include elevated CRP and IL-6 in patients at the time of hospitalization who eventually died (29) and increased IP-10 in those who later developed severe disease (30). IP-10 is an interferon-inducible chemokine that facilitates directed migration of many immune cells (31) and is elevated in other coronavirus infections including MERS-CoV and SARS-CoV (32), as well as in Influenza virus of swine origin (H1N1) (33, 34). The heightened levels of monocyte-chemoattractant protein 1 (MCP-1) upon admission further indicate dysregulation of monocyte function and migration in patients with severe disease. Importantly, IL-6, IP-10 and MCP-1 levels are generally the highest around the time of hospital admission but are reduced rapidly as patients are admitted to intensive care, which may well signify exhaustion of the immune cells producing these mediators.

Examining cells of the adaptive immune system, we identified lymphopenia which is now a well-established hallmark of COVID-19 patients (3538). Despite this being a key feature of COVID-19, the drivers of loss of T and B cell numbers in peripheral blood remain obscure and could equally reflect either cell death and/or elevated trafficking to the site of inflammation. Focusing on T cells, the phenotype and function of circulating T cells remain an issue with conflicting reports within the literature. Consistent with previous reports, our data show modest increases in T cell activation (27, 39, 40), primarily driven by a substantial heterogeneity between patients. Despite this, the frequencies of T cells with activated phenotypes remained stable across the disease trajectory, implying most changes to these adaptive mediators could have occurred prior to hospitalization. Importantly our data highlight activation of a cytotoxic program in CD8+ T cells, evidenced by perforin expression, which would support effective viral clearance that has previously been suggested (41). Focusing on B cells, patients with severe COVID-19 displayed a dramatic expansion of CD27IgD double negative (DN) B cells. This is in agreement with a recent study reporting lupus-like hallmarks of extrafollicular B cell activation in critically unwell COVID-19 patients (42). DN B cells are also associated with immune senescence as a result of excessive immune activation, and an exhausted phenotype is observed in patients with HIV (11). Further studies evaluating the functional capacity of expanded DN B cells will be critical to understand their contribution to severe COVID-19.

There are, of course, limitations to any study of samples during a viral pandemic for which there is no vaccine. However, we believe that these do not diminish the importance of the major findings from our study. A longitudinal analysis in real time for phenotypic, functional and soluble markers naturally limits the number of patients interrogated. In-depth analysis of smaller cohorts however, is necessary to gain insight into mechanism and is of interest to the pharmaceutical industry. It takes time to recruit the appropriate number of control subjects of the approximate gender and age of COVID patients and also with the span of comorbidities associated with the greatest risk from SARS-CoV-2. The majority of our controls were drawn from frontline workers, who produced remarkably similar results to each other. The only other potential limitation is that patients may not accurately define the onset of symptoms. As data are plotted per patient, however, this does not affect the interpretation of the results.

There are clinical implications of our data. Using non-steroidal anti-inflammatory drugs (NSAIDs) remains controversial (43) and our study would suggest they may not be desirable, as this may compound the already low COX-2 (44). Since most of the pathogenic mechanisms involve myeloid cells, neutrophils and monocytes, it would be advantageous to reduce their influx to the lung once lung pathology is established. Relevant strategies include inhibition of the complement anaphylatoxin C5a (45) or IL-8 (CXCL8), which are strong chemoattractants for many immune cells, including neutrophils. Antagonism of CXCR2 that mobilizes neutrophil and monocyte from the bone marrow, neutrophil elastase inhibitors and inhibition of G-CSF, IL-23 and IL-17 that promote neutrophil survival, are also options (46). Anti-IL-6, IL-1RA and anti-TNF- agents are already being investigated for COVID-19 treatment and are relevant to neutrophils, which express the requisite cytokine receptors. Furthermore, JAK inhibitors are currently in clinical trials and may also reduce neutrophil levels (47). Targeting toxic products of neutrophils such as S100A1/A2, HMGB1 and free radicals, but also the formation of NETs, could be beneficial (21).

In summary, this is a key longitudinal study immune profiling COVID-19 patients that places equal emphasis on innate and adaptive immunity. We identify substantial alterations in the myeloid compartment in COVID-19 patients that have not previously been reported. It would appear that comparable innate immune features have been evident in past pandemics with similar or even different viruses and so focusing immune modulation strategies on neutrophils and monocytes is an urgent priority.

Between 29th March and 7th May, 2020, adults requiring hospital admission with suspected COVID-19 were recruited from 4 hospitals in the Greater Manchester area. Our research objective was to undertake an observational study to (1) examine the kinetics of the immune response in COVID-19 patients and (2) identify early indicators of disease severity. Informed consent was obtained for each patient. Peripheral blood samples were collected at Manchester University Foundation Trust (MFT), Salford Royal NHS Foundation Trust (SRFT) and Pennine Acute NHS Trust (PAT) under the framework of the Manchester Allergy, Respiratory and Thoracic Surgery (ManARTS) Biobank (study no M2020-88) for MFT or the Northern Care Alliance Research Collection (NCARC) tissue biobank (study no. NCA-009) for SRFT and PAT (REC reference 15/NW/0409 for ManARTS and 18/WA/0368 for NCARC). Clinical information was extracted from written/electronic medical records. Patients were included if they tested positive for SARS-CoV-2 by reverse-transcriptasepolymerase-chain-reaction (RT-PCR) on nasopharyngeal/oropharyngeal swabs or sputum. Patients with negative nasopharyngeal RT-PCR results were also included if there was a high clinical suspicion of COVID-19, the radiological findings supported the diagnosis and there was no other explanation for symptoms. Patients were excluded if an alternative diagnosis was reached, where indeterminate imaging findings were combined with negative SARS-CoV-2 nasopharyngeal (NP) test or there was another confounding acute illness not directly related to COVID-19. The severity of disease was scored each day, based on degree of respiratory failure (Fig. 1B). Patients were not stratified for disease severity if there was no available clinical observation data or patients were recruited more than 7 days after hospital admission. Where severity of disease changed during admission, the highest disease severity score was selected for classification. The first available time point was used for all cross-sectional comparisons between mild, moderate and severe disease. Peripheral blood samples were collected as soon after admission as possible and at 1-2 day intervals thereafter. For longitudinal analysis we elected to correlate clinical data with immune parameters directly, rather than using the WHO ordinal scale on account of the small range of values this affords our inpatient cohort, which our study would not be powered to discern. Healthy blood samples were obtained from frontline workers at Manchester University and NHS Trusts (age range 28-69; median age=44.5 years; 42.5% males). Samples from healthy donors were examined alongside patient samples.

Whole venous blood was collected in tubes containing EDTA or serum gel clotting activator (Starstedt). Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation using Ficoll-Paque Plus (GE Healthcare) and 50 ml SepMate tubes (STEMCELL technologies) according to the manufacturers protocol. Serum was separated by centrifuging serum tubes at 2000 g at 4C for 20 min.

Red blood cell lysis was carried out using 10x volume of distilled water for 10 s followed by addition of 10x PBS to re-establish a 1x PBS solution and stop lysis. Cells were centrifuged at 500 g for 5 min and lysis repeated if necessary.

White blood cells from lysed whole blood and isolated PBMCs separated by density gradient centrifugation were stained immediately on receipt. The following antibodies were used: BDCA-2 (clone 201A), CCR7 (clone G043H7), CD11b (clone ICRF44), CD11c (clone 3.9 or Bu15), CD123 (clone 6H6), CD14 (clone 63D3), CD16 (clone 3G8), CD19 (clone H1B19), CD24 (clone M1/69 or ML5), CD27 (clone M-T271), CD3 (clone OKT3 or UCHT1), CD38 (clone HIT2), CD4 (clone SK3), CD45 (clone 2D1), CD45RA (clone HI100), CD56 (clone MEM-188), CD62L (clone DREG-56), CD8 (clone SK1), HLA-DR (clone L234), ICOS (clone C398.4A), IgD (clone IA6-2), IgM (clone MHM-88), IgG (clone M1310G05), Ki-67 (clone Ki-67 or 11F6), PD-1 (clone EH12.2H7), perforin (clone dG9), CD66b (clone G10F5), CD64 (clone 10.1), IL-1 (clone H1b-98) and TNF- (clone MAb11), all from Biolegend; and COX-2 (clone AS67) from BD Biosciences. PBMCs were also stimulated in vitro for 3 hours with 10 ng/ml LPS in the presence of 10 g/ml brefeldin A to allow accumulation and analysis of intracellular proteins by flow cytometry. Cells were cultured in RPMI containing 10% fetal calf serum, L-Glutamine, Non-essential Amino Acids, HEPES and penicillin plus streptomycin (Gibco). For surface stains samples were fixed with BD Cytofix (BD Biosciences) prior to acquisition and for intracellular stains (Ki-67, COX-2, TNF- and IL-1) the Foxp3/Transcription Factor Staining Buffer Set (eBioscience) was used. All samples were acquired on a LSRFortessa flow cytometer (BD Biosciences) and analyzed using FlowJo (TreeStar).

Thirteen different mediators associated with anti-viral responses were measured in serum using LEGENDplex assays (BioLegend, San Diego, USA) according to the manufacturer's instructions.

Results are presented as individual data points with medians. Statistical analysis was performed using Prism 8 Software (GraphPad). Normality tests were performed on all datasets. Groups were compared using an unpaired t-test (normal distribution) or Mann-Whitney test (failing normality testing) for healthy individuals versus COVID-19 patients. Paired t-test (normal distribution) or Wilcoxon matched-pairs signed rank test (failing normality testing) was used for longitudinal data where first and last time points were examined. One-way ANOVA with Holm-Sidak post-hoc testing (normal distribution) or Kruskal-Wallis test with Dunns post-hoc testing (failing normality testing) was used for multiple group comparisons. Correlations were assessed with Pearson correlation coefficient (normal distribution) or Spearmans rank correlation coefficient test (failing normality testing) for separate parameters within the COVID-19 patient group. Information on tests used is detailed in figure legends. In all cases, a p-value of 0.05 was considered significant. ns, not significant; p < 0.05, p < 0.01, p < 0.001.

immunology.sciencemag.org/cgi/content/full/5/51/eabd6197/DC1

Figure S1. Immune cell types in COVID-19 patients.

Figure S2. Serum cytokines and chemokines in COVID-19 patients.

Figure S3. T cell activation in COVID-19 patients.

Figure S4. B cell subsets in COVID-19 patients.

Figure S5. Monocytes in COVID-19 patients.

Table S1. Raw data file (Excel spreadsheet).

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19 - Science

New research at Washington University School of Medicine in St. Louis helps illuminate a surprising mind-body connection. In mice, the researchers found that immune cells surrounding the brain produce a molecule that is then absorbed by neurons in the brain, where it appears to be necessary for normal behavior.

The findings, published Sept. 14 inNature Immunology, indicate that elements of the immune system affect both mind and body, and that the immune molecule IL-17 may be a key link between the two.

"The brain and the body are not as separate as people think," said senior author Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology and Immunology and a professor of neurosurgery, of neurology and of neuroscience. "What we've found here is that an immune molecule -- IL-17 -- is produced by immune cells residing in areas around the brain, and it could affect brain function through interactions with neurons to influence anxiety-like behaviors in mice. We are now looking into whether too much or too little of IL-17 could be linked to anxiety in people."

IL-17 is a cytokine, a signaling molecule that orchestrates the immune response to infection by activating and directing immune cells. IL-17 also has been linked to autism in animal studies and depression in people.

How an immune molecule like IL-17 might influence brain disorders, however, is something of a mystery since there isn't much of an immune system in the brain and the few immune cells that do reside there don't produce IL-17. But Kipnis, along with first author and postdoctoral researcher Kalil Alves de Lima, PhD, realized that the tissues that surround the brain are teeming with immune cells, among them, a small population known as gamma delta T cells that produce IL-17. They set out to determine whether gamma-delta T cells near the brain have an impact on behavior. Kipnis and Alves de Lima conducted the research while at the University of Virginia School of Medicine; both are now at Washington University.

Using mice, they discovered that the meninges are rich in gamma-delta T cells and that such cells, under normal conditions, continually produce IL-17, filling the tissues surrounding the brain with IL-17.

To determine whether gamma-delta T cells or IL-17 affect behavior, Alves de Lima put mice through established tests of memory, social behavior, foraging and anxiety. Mice that lacked gamma-delta T cells or IL-17 were indistinguishable from mice with normal immune systems on all measures but anxiety. In the wild, open fields leave mice exposed to predators such as owls and hawks, so they've evolved a fear of open spaces. The researchers conducted two separate tests that involved giving mice the option of entering exposed areas. While the mice with normal amounts of gamma-delta T cells and levels of IL-17 kept themselves mostly to the more protective edges and enclosed areas during the tests, mice without gamma-delta T cells or IL-17 ventured into the open areas, a lapse of vigilance that the researchers interpreted as decreased anxiety.

Moreover, the scientists discovered that neurons in the brain have receptors on their surfaces that respond to IL-17. When the scientists removed those receptors so that the neurons could not detect the presence of IL-17, the mice showed less vigilance. The researchers say the findings suggest that behavioral changes are not a byproduct but an integral part of neuro-immune communication.

Although the researchers did not expose mice to bacteria or viruses to study the effects of infection directly, they injected the animals with lipopolysaccharide, a bacterial product that elicits a strong immune response. Gamma-delta T cells in the tissues around the mice's brains produced more IL-17 in response to the injection. When the animals were treated with antibiotics, however, the amount of IL-17 was reduced, suggesting gamma-delta T cells could sense the presence of normal bacteria such as those that make up the gut microbiome, as well as invading bacterial species, and respond appropriately to regulate behavior.

The researchers speculate that the link between the immune system and the brain could have evolved as part of a multipronged survival strategy. Increased alertness and vigilance could help rodents survive an infection by discouraging behaviors that increase the risk of further infection or predation while in a weakened state, Alves de Lima said.

"The immune system and the brain have most likely co-evolved," Alves de Lima said. "Selecting special molecules to protect us immunologically and behaviorally at the same time is a smart way to protect against infection. This is a good example of how cytokines, which basically evolved to fight against pathogens, also are acting on the brain and modulating behavior."

The researchers now are studying how gamma-delta T cells in the meninges detect bacterial signals from other parts of the body. They also are investigating how IL-17 signaling in neurons translates into behavioral changes.

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Could Our Immune System Alter Behavior? - Technology Networks

Most of us will be familiar with the sort of stress that leads to sleepless nights. In new research on mice, scientists have now identified the brain circuit involved in such experiences; moreover, this part of the brain also seems to be linked to a stress-induced weakening of the immune system.

Immunity, stress, and sleep could all be connected by this same circuit of neurons, researchers say, though so far the connection has only been discovered in mice. If this link is also present in humans, treatments could be developed to target it.

"This sort of stress-induced insomnia is well known among anybody that's tried to get to sleep with a looming deadline or something the next day," says neuroscientist Jeremy Borniger, from Cold Spring Harbor Laboratory (CSHL) in New York.

"And in the clinical world, it's been known for a long time that chronically stressed patients typically do worse on a variety of different treatments and across a variety of different diseases."

The stress hormone cortisol is thought to be responsible for disrupting sleep and damaging the body's immune system. The first discovery in this research was a link between a group of cortisol-releasing neurons sensitive to stress, and a group of neurons associated with insomnia.

When the link was blocked by the researchers, mice were able sleep peacefully even after a stressful experience. On the flip side, stimulating the stress-sensitive neurons was enough to bring the animals out of their slumber.

"It seems like it's a pretty sensitive switch, in that even very weak stimulation of the circuit can drive insomnia," says Borniger.

Borniger and his colleagues were then able to establish that stimulating this part of the brain was also producing a biological reaction that looked a lot like the standard immune response to stress.

Messing with this circuit also disrupted the way cortisol is released from the brain, leading to changing levels of immune cells and a breakdown in signalling between them. It looks as though the same group of stress-related neurons drive the consequences for both sleep and immunity.

Systemic inflammation where the body's defences mistakenly go into overdrive when they don't need to is associated with a variety of diseases and health problems, from cancer to inflammatory bowel disease and psoriasis. This new discovery might one day give us another way to fight it.

"If we can understand and manipulate the immune system using the natural circuitry in the body rather than using a drug that hits certain targets in the system, I think that would be much more effective in the long run," says Borniger.

The research has been published in Science Advances.

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One Brain Circuit Links Stress, Sleep And The Immune System, Mouse Study Reveals - ScienceAlert