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Archive for the ‘Immune System’ Category

Your immune system responds very differently to a ‘breakthrough’ Covid-19 infection – The Daily Briefing

Wednesday, August 4th, 2021

It's "an arithmetic inevitability" that some people vaccinated against the coronavirus will contract so-called "breakthrough" infectionsbut a vaccinated person's immune system responds to the virus in distinctive ways that dramatically reduce the risk of serious disease, Katherine J. Wu writes for The Atlantic.

Your top resources on the Covid-19 vaccines

According to the Washington Post, it's difficult to track the absolute rate of breakthrough infections, both because many such infections are asymptomatic and because surveillance testing has declined in areas where vaccines are readily available.

It's clear, however, that breakthrough infections are uncommon and very rarely cause serious disease. According to CDC director Rochelle Walensky, 97% of all Covid-19 hospitalizations and 99.5% of all Covid-19 deaths are currently among the unvaccinated.

So why are breakthrough infections so much milder? It's because a vaccinated person's immune response looks very different than an unvaccinated person's, Wu writes.

When an unvaccinated person is exposed to the coronavirus, Wu writes, their only protection comes from the body's innate defenders, which are "short-lived and woefully imprecise."

"They'll sink their teeth into anything they don't recognize, and are easily duped by stealthier invaders," Wu writes, making them "a pretty flimsy first line of defense."

If left to its own devices, an unvaccinated person's so-called "adaptive" immune system will eventually develop a more powerful, customized response to the coronavirusbut it can take weeks to do so.

By then, Wu writes, "the virus may have run roughshod over everything it can." It may be too late for the immune system to prevent serious long-term damage or even death.

By contrast, a vaccinated person's immune system has already been trained to mount that more powerful, adaptive response. Vaccine shots "act as confidential informants, who pass around intel on the pathogen" before an infection occurs, Wu writes.

In particular, vaccination prepares the body's adaptive B cells to more quickly produce antibodies when they encounter the coronavirus, and T cells can more quickly target and kill off infected cells. This enables a vaccinated person to mount a powerful immune response much more quickly.

"In the best-case scenario, the virus might even be instantly sniped at by immune cells and antibodies," Wu writes. But even if the virus overwhelms the body's initial defenses, the vaccine has prepared the body to mount a fuller response.

"A breakthrough, despite what it might seem, does not cause our defenses to crumble or even break," Wu writes. "[I]t does not erase the protection that's already been built."

Rather, according to Deepta Bhattacharya, an immunologist at the University of Arizona, the virus must overcome "backup layer after backup layer" of defenses. So even if a virus continues to spread through a person's body, "[e]ach stage it has to get past takes a bigger chunk" out of it, Bhattacharya said.

That's why people who have been vaccinated tend to experience fewer and milder symptoms and recover more quickly, Wu writes.

"People tend to think of this as yes or noif I got vaccinated, I should not get any symptoms; I should be completely protected," Laura Su, an immunologist at the University of Pennsylvania, said. "But there's way more nuance than that."

"The vaccines were developed to keep us out of those terrible institutions we call hospitals," William Schaffner, an infectious disease expert at Vanderbilt University, said. "We have to keep coming back to that." (Gale, Washington Post, 7/25; AP/Modern Healthcare, 7/21; Cohen, Forbes, 7/22; Wu, The Atlantic, 7/26)

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Your immune system is not ready for the office – Wired.co.uk

Wednesday, August 4th, 2021

Get ready to have a cold. Thats the message from doctors, immunologists, virologists and architects as England emerges from lockdown.

An amalgamation of 16 months cooped up inside, a culture of showing up to work despite sickness, and woefully outdated building infrastructure in the UK is set to become a pressure cooker for viruses. The country at large is about to experience the rush of a kind of post-lockdown Freshers Flu.

Never before in modern human history have we had global distancing, social distancing, mask wearing, quarantining and isolating, says Gregory Poland, head of the Vaccine Research Group at the Mayo Clinic in the US. Its going to be an interesting experiment of nature to see what happens when you stop the circulation of those viruses for a season.

Like Covid, colds are spread through inhaling droplets from the air, and also by touch. Under normal circumstances, the average adult has between two and four colds a year, while children have between six and eight. These move easily between people and can be contagious for up to two weeks after symptoms appear.

Pre-pandemic, our bodies were often exposed to viral respiratory pathogens. Sometimes these made us sick, and other times they boosted our immune responses. But lockdowns, increased hand washing, and masks may have dulled this risk and left a hole in our natural defences.

The hygiene hypothesis posits that early exposure to a variety of germs builds better immunity for life. As such, evidence suggests children who are exposed to lots of different microbes are less likely to develop allergies and autoimmune disorders. Bodies remember responses to viruses and bacteria, and are able to mobilise and protect us against them. Our immune systems may struggle with new, cold-causing viruses in circulation, though, meaning we will still get sick, but the immune response will still know how to fight it even after lockdowns.

There are, however, other variables to consider. Whether you are getting enough vitamin D, are stressed, or have been particularly lonely could also factor into your anti-viral response. An analysis of studies monitoring more than 300,000 people found that people who are more socially connected are 50 per cent less likely to die over a given period. Research has also shown that people with lots of social ties are even less susceptible to the common cold. Stress, which produces cortisol, also harms immune function.

Rates of colds in the UK are difficult to track; they rarely cause hospitalisations, and people are encouraged to ride them out rather than visiting their GP. However, scientists can make a good guess at what is set to hit the northern hemisphere due to patterns happening in the south. Australia has already seen a resurgence of respiratory illnesses other than Covid, as have parts of the US.

In the US, numbers of cases of respiratory syncytial virus (RSV) a type of virus that infects the lungs and commonly causes hospitalisations in children have headed upwards in recent weeks, with around 1,600 confirmed cases nationally in the week of July 17, and 2,000 the week before. In the week of 25 July a year ago there were only 11 RSV cases recorded by the Centers for Disease Control (CDC).

Similarly in Australia, a surge in RSV cases was seen in spring in states such as New South Wales and Western Australia, followed by rising rates in Queensland and Victoria. They were at an all-time low throughout the Australian winter.

The Royal Australian College of General Practitioners warned that, as in Australia, relaxing of Covid restrictions may provide an opportunity for rapid spread of RSV. Our experience should serve as a warning for paediatric hospitals in the Northern Hemisphere to ensure adequate staffing and available resources to meet the possible increased need, it wrote.

Add in pressure to attend the office even when people are feeling unwell, and youve got a recipe for transmission. A report from the ADP Research Institute showed that, during the pandemic, more than half (54 per cent) of employees globally have felt pressure from their employer to come into work at some point, even though the official line has been to stay home.

Meanwhile, the government has repeatedly encouraged a return to offices for non-essential workers in-between lockdowns, trading off trying to reignite the economy and get people back into Pret a Mangers with the risk of breathing new life into Covid caseloads.

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How many antibodies does it take to be immune to the coronavirus? – Hindustan Times

Wednesday, August 4th, 2021

Antibodies are crucial for vaccination to work, but scientists don't yet know what level they must reach. The new delta variant poses another problem.

After a coronavirus infection or a vaccination, the body produces antibodies against the virus's spike protein, which SARS-CoV-2 uses to dock onto the cells and penetrate them. This spike protein allows antibodies to recognize the virus and bind to it, making it visible to immune cells.

Scientists previously assumed that people vaccinated with mRNA vaccines such as the one produced by BioNTech-Pfizer had more than 90 per cent protection against the virus - but that does not apply to the new delta variant. This variant is much more contagious than the ancestral virus and is spreading all over the world.

ALSO READ: Pfizer, AstraZeneca vaccine antibody levels may wane after 2-3 months: Study

Carsten Watzl, an immunologist at the Leibniz Institute of the Dortmund Technical University, estimates that the effectiveness of BioNTech-Pfizer mRNA vaccines has reduced from 90 per cent, in the case of the original virus, to 88 per cent with delta. The AstraZeneca vector vaccine's effectiveness has gone from 66 per cent to 60 per cent.

Data from Israel indicates that protection against infection with the dangerous variant is only about 64 per cent when the BioNTech-Pfizer vaccine is used. But the vaccine still offers 93 per cent protection against a severe case of Covid-19. The Israeli Health Ministry is now considering offering people a third dose of the vaccine.

Measurement difficulties

After two shots, the majority of the people are immune to the virus variants known so far - but Carsten Watzl cautions that this does not necessarily apply to everyone who is double-vaccinated.

"Vaccination alone is no guarantee for being immune," he says, adding that what matters is whether the body has built up sufficient immune protection. "But we can't measure that at the moment," he says.

This is different from a tetanus vaccination, where tests can determine whether or not a body is sufficiently protected. A lab checks the blood for the level of antibody titers. If the number of antibodies is above a certain threshold, the person is immune to the tetanus virus. If the titer is too low, the patient needs a booster shot.

With the coronavirus, researchers have not yet reached that stage, Watzl says. "We don't know yet exactly what we need to measure to really determine whether someone is immune or not. Presumably, the neutralizing antibodies play a key role - they bind the virus in such a way that it cannot infect any more cells."

But it is unclear how high the number of these antibodies has to be, he adds.

What do the T cells do?

Only antibodies are not essential in the fight against infection. Once the virus has entered the cell, the antibodies can no longer reach it, because they cannot go into the cell. So, the virus will replicate.

"To fight that, our immune system has T cells; they are able to kill such virus-infected cells - in other words, we would rather sacrifice a few cells in our body, namely the infected ones, than give the virus the opportunity to multiply," Watzl says.

Both these processes can be measured. In practice, however, it is more difficult to determine the number of T cells than that of antibodies. The T cell test is relatively time-consuming but quite useful.

"The antibodies alone don't necessarily tell you anything about how well you are protected," says Watzl: He says that a person might have hardly any antibodies and so could still become infected with the virus. "But the response of the T cells is so strong that the person doesn't get seriously ill," he says.

People with a high level of antibodies are probably well protected against the coronavirus, the immunologist added. But the reverse conclusion - that few antibodies mean no protection - is probably not true, according to him.

A matter of levels

Coronavirus antibody tests employ various measurement methods. Normally, laboratory tests use a clear standard stipulating a minimum to a maximum value. This allows a doctor to see whether levels are within the normal range. The levels have not yet been defined for the coronavirus, however.

So, doctors approximate, with measured levels ranging from less than a hundred to several thousand antibodies. "If I am in the upper third or in the upper half, I probably have good immune protection. But I can't give you the exact threshold values yet," Watzl says.

It is not clear how quickly antibody levels drop, only that they do drop over time.

"It moves in two waves - if you look at the levels right after vaccination, you have the highest antibody level. In the first few months after vaccination, that level decreases relatively quickly. At some point, the whole thing settles at a certain value, and only drops very slowly from there," Watzl says, adding that scientists are familiar with this phenomenon from other vaccinations. "It appears to be true for the coronavirus vaccine, too; science just hasn't proven that yet," he says.

More is better

Some people who have been vaccinated twice have hardly any antibodies against the virus, so they are probably not properly protected, warns Watzl. Low antibody levels can be due to age or a suppressed immune system. Often patients need a third vaccination for the body to form antibodies at all.

Observations range from people who have many antibodies and are well protected to people who have too few antibodies and are poorly protected to people with few antibodies who are still protected.

The conclusion so far is that no one knows for sure. But Watzl is optimistic, emphasizing that "more is better."

"We don't know yet what the threshold levels are, and what level it takes to be protected," he says. "But we will get there someday."

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An evolving discipline: Evolutionary medicine brings together biological anthropology and public health | Binghamton News – Binghamton University

Wednesday, August 4th, 2021

An evolutionary arms race churns away under your skin sometimes quietly and unnoticed, other times with the ferocity of an embattled immune system repelling the invader.

Both sides in this war harmful parasites, viruses and bacteria on one hand, and your immune system on the other are looking to access a critical resource and keep it out of the others possession. That resource is iron, which every cell in your body needs to power its metabolism, as do the infectious agents that seek to exploit it. When one side evolves a battle strategy, the other evolves a way to defeat it something we are seeing in real time with the emergence of coronavirus variants.

Evolutionary medicine, a field within biological anthropology that first emerged in the 1990s, takes a large-scale view of the mechanisms behind human disease and health. By studying the evolution of humanity how early humans lived and the environments they lived in we begin to understand the factors that contribute to disease, which can lead to treatments or prevention today, explained Associate Professor of Anthropology Katherine Wander.

Thats where my interests in human biology and biology and my interest in public health come together, she said.

Wanders research touches on a wide array of topics: iron deficiency and infectious disease risk in Tanzania and Nigeria, the social determinants of disease in Bangladesh and among the matriarchal Mosuo people in China, human adaptations to living at high altitudes and the impact on chronic disease risk, the effect of adoption and fosterage on child health in the island nation of Vanuatu.

The sheer diversity can make it difficult to explain her research in two sentences, she admits.

Thats one of the best things about biomedical anthropology: you can research the things youre interested in. You dont have to stay in one lane, she said. You have to do your background research to be able to contribute to knowledge in a new area, but it doesnt hurt my career to be doing a lot of different things.

Evolutionary approaches to health are common in pop science articles, but these types of publications frequently rely on speculation and the latest trends. Even with a topic such as nutrition, the science is complex and nuanced, including such factors as the evolution of the human gut and innovations such as cooking, which increased our ability to extract nutrients.

Associate Professor of Anthropology Katherine Wander in her lab. Image Credit: Jonathan Cohen.We make a lot of assumptions about what ancient humans did and what we should do as a result. But we dont really know; we need to systematically study that, Wander said.

Ancient humans didnt live in utopia; they frequently met early deaths, Wander pointed out. Natural and healthy also arent equivalent; human beings, for example, evolved in tandem with diseases such tuberculosis that continue to kill people today although to a much lesser extent, due to the invention of modern medicines and vaccines.

In fact, humans today do many things right; our children often survive to adulthood, for example, which wasnt always the case. And there arent many species and no other primates that can occupy as many different environments as humans, from deserts to tundra.

While Wanders interests are wide-ranging, basic questions lie at the heart of her research: Why do children get sick? And what could we do to prevent that, from an evolutionary perspective?

These basic questions often lead to others. In her iron deficiency-related projects in sub-Saharan Africa, she is exploring what constitutes an optimal iron level, especially for a child in an environment with exposure to many infectious diseases.

On one end of the spectrum is anemia, in which low iron levels compromise the production of hemoglobin; on the other end, the individual might be iron replete, with plenty of iron available for their own cells and for those of infectious agents. Where on that spectrum is the lowest risk of infectious disease? Where is the potential for optimal brain development and growth?

A topic as elemental as iron and its role in disease also can lead to entirely new avenues. Wander recently received funding from the National Science Foundation to look at how iron levels affect coronavirus risk in healthcare workers, for example; researchers are still collecting data for that project.

Prospective students in the biomedical anthropology program need to be willing to ask questions both to explore their interests and find training opportunities. Whether youre interested in the skeletal remains of ancient human populations, public health in a specific area, cultural perspectives on health or health culture, or the genetic mechanisms of disease, you can find the path that works for you.

As a result, program graduates can look incredibly different from one another: Some might find their calling in a coroners office, others in public health, research or more.

For graduate students interested in the discipline, Wander is a ready guide. They have joined her in Tanzania to conduct research, and analyze samples connected with projects from around the world in her Binghamton lab. Students are also encouraged to pursue internships in the field and to start building the connections that will enliven their future careers.

Humans, after all, have evolved to be a cooperative species. In an interdisciplinary field such as evolutionary medicine, collaborating with colleagues and mentors can spark new ideas, leading to exciting and unexpected new directions.

Sitting by yourself, making all of the decisions on a project isnt nearly as fun as collaborating with a big group of people who have a lot of different ideas about what data you should collect and why, Wander said.

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I’m A Functional MD: Here’s Why You Should Focus On Your "Immune Kettle" – mindbodygreen.com

Wednesday, August 4th, 2021

So what goes into it? According to Bock, there are a lot of different layers, with the first being your basic genetic predispositions, which we can't control.

On top of that, there are the factors that we can control, like stress, diet, environmental toxins, and more. "I think stress is very important," he says. "The value of the immune kettle is that, yes, frequently stress may be the largest component of the immune count."

Then you add in factors like allergies, sensitivities, hormone imbalances, and of course, big infections. "These are things that can really add layers to the immune kettle. And the key is that these layers can be different sizes," he explains. "So if they're small, they're low. The lower you reside in the immune kettle."

Importantly, Bock notes that, depending on how well you handle stress, it could be the very factor that puts you over the edge, to your kettle's boiling point. An overload of stress, he says, is what increases many people's susceptibility to illness.

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No, people who recovered from COVID-19 are not completely immune to the virus – Local 5 – weareiowa.com

Wednesday, August 4th, 2021

Although studies show people who had COVID-19 and survived have some level of immunity, public health agencies still recommend they get vaccinated.

COVID-19 cases, hospitalizations and deaths are again rising across the United States, with the highest spread coming in areas with low vaccination rates, according to the Centers for Disease Control and Prevention. The increase in cases has come with the continued spread of the more contagious delta variant.

As a result, the CDC and Democratic and Republican leaders are urging more people to get vaccinated. But what about people who already had COVID-19? A VERIFY viewer asked if they are immune and wondered if they should get vaccinated.

THE QUESTION

Maria C. asked: Are people who recovered from COVID-19 completely immune?

THE SOURCES

THE ANSWER

No, people who recovered from COVID-19 are not completely immune to the virus and health officials recommend they get vaccinated.

WHAT WE FOUND

The World Health Organization says: Take whatever vaccine is made available to you first, even if you have already had COVID-19. It is important to be vaccinated as soon as possible once its your turn and not wait. Approved COVID-19 vaccines provide a high degree of protection against getting seriously ill and dying from the disease, although no vaccine is 100% protective.

The CDC alsorecommends people who already had COVID-19 get vaccinated. People who were treated with monoclonal antibodies or convalescent plasma should wait 90 days before getting vaccinated, the CDC says. But after that, the agency recommends those people get the vaccine as well.

Dr. Bill Moss, a professor and executive director of the International Vaccine Access Center at Johns Hopkins University, said immunity means a persons immune system has previously responded to a bacteria or virus that causes infection.

However, its more of a spectrum than an absolute, as there are different levels of immunity,he said.

People who were infected with COVID-19 and survived have some level of natural immunity, although the CDC says its unclear how long that protection lasts. The CDC saysreported cases of reinfection are rare.

One study, partially funded by the National Institutes of Health, concluded immunity may last as long as eight months after infection.Dr. Abinash Virk with the Mayo Clinic said recent studies show natural immunity may last for at least a year. But she said the COVID-19 vaccines boost immunity for people who already had COVID-19 and provide protection against variants of concern.

"Additionally, vaccinated persons have demonstrated longer immunity and lower rates of infection than those who were infected, suggesting the vaccines generate a more sustained immunity than natural infection alone, Virk said.

The CDC says studies suggest the currently authorized vaccines, developed by Pfizer, Moderna and Johnson & Johnson,work against the variants, including the widespread delta variant, which is estimated to make up more than80% of new COVID-19 cases across the U.S.

As of Aug. 2,nearly 50% of the U.S. population was fully vaccinated against COVID-19. More than 611,000 COVID-19 deaths have been reported in the U.S. during the pandemic.

The VERIFY team works to separate fact from fiction so that you can understand what is true and false. Please consider subscribing to our daily newsletter, text alerts and our YouTube channel. You can also follow us on Snapchat, Twitter, Instagram, Facebook and TikTok. Learn More

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Genetic mutation linked to rare inflammatory bowel disease bowel-disease – Health Europa

Wednesday, August 4th, 2021

Scientists from Johns Hopkins Medicine, in collaboration with national and international researchers, have identified a genetic mutation in a small number of children with a rare type of inflammatory bowel disease. They say that this discovery could help to define the cause of more common bowel diseases and lead to more targeted treatments for gut conditions.

The study has been published in Human Genetics.

Anthony Guerreiro Jr., M.D, Ph.D., M.S., Director of the Very Early Onset Inflammatory Bowel Disease Clinic and Assistant Professor of Pediatrics at the Johns Hopkins University School of Medicine, said: We aimed to see if children have a greater genetic susceptibility for this type of inflammatory bowel disease because they develop it so young,

Unlike other inflammatory bowel diseases, very early onset inflammatory bowel disease is diagnosed in patients before the age of six, occurring in four out of every 100,000 births worldwide. In such young patients, the disease does not typically respond to anti-inflammatory medications, and surgery is sometimes required to remove all or parts of the colon.

Inflammatory bowel diseases are chronic, inflammatory conditions including Crohns disease and ulcerative colitis that occur when immune cells in the intestines are overactivated, causing sustained inflammation in the gut. These diseases are thought to be caused by multiple genetic mutations and environmental factors, such as diet and pollution, as well as disruptions to the makeup of gut bacteria. Common treatments include prescription drugs that curb inflammation.

Since the most common characteristic of bowel diseases is inflammation, scientists have long suspected genetic links between the immune system and bowel conditions.

In the study, scientists collected tissue samples from 24 patients with very early onset inflammatory bowel disease seen at The Johns Hopkins Hospital and Johns Hopkins Childrens Center and performed whole exome sequencing a method that looks at the protein-producing areas of a gene to identify mutations.

Of the 24 patients, mutations were found in four patients in parts of a gene called IFIH1, which produces a protein involved in the virus-fighting branch of the immune system. Other genetic sequencing studies have also linked the IFIH1 gene to inflammatory bowel diseases, and the current research backs up the genes involvement in very early onset inflammatory bowel disease.

As the number of patients in the first round of sequencing was small, the researchers turned to a Johns Hopkins-developed online database called GeneMatcher, which contains genetic variations from people worldwide. Guerrerio and GeneMatcher co-founder Nara Sobreira, M.D, Ph.D, Assistant Professor of Genetics and Pediatrics at the Johns Hopkins University of Medicine, found an additional 18 patients with very early onset inflammatory bowel disease being studied at both the NIH and in Padova, Italy.

The combined research teams found IFIH1 mutations in four of the 18 new patients, bringing the total of IFIH1 mutations found to eight out of the 42 patients. Among the IFIH1 mutations, the researchers discovered nine mutations which resulted in abnormal production of a protein called MDA5. In the eight patients with the mutations, MDA5 function was much lower than normal.

When functioning properly, MDA5 is a part of the inborn immune system that helps fight off viruses in the gut. Using protein assays that mimicked the activity of normal and abnormal MDA5, the researchers found that, in each patient with the IFIH1 mutation, the MDA5 proteins only partially worked, but not enough to do their job of battling viruses. The researchers suspect this loss of function in the protein causes the improper activation of the immune system, triggering the inflammation that leads to very early onset inflammatory bowel disease.

The researchers also believe that the partially functioning MDA5 proteins protect patients from more severe and rare immune diseases, such as Singleton-Merton syndrome and Aicardi-Goutires syndrome, that are associated with no MDA5 production.

Sobreira said: When you look at the physical changes associated with IFIH1 mutations, there are a wide range and they are really very different.

Its crucial to know that these different variations in the same gene can cause these different characteristics.

The researchers hope that their findings will help to improve understanding of the genetic cause of diseases and inform treatment options. They also believe the research provides additional evidence of the link between inflammatory bowel diseases and the virus-fighting part of the bodys immune response.

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If Ive already had Covid, do I need a jab? How does the immune system respond? An expert explains – News24

Wednesday, August 4th, 2021

Over a year into the pandemic, questions around immune responses after Covid continue to confound.

One question many people are asking is whether the immunity you get from contracting Covid and recovering is enough to protect you in the future.

The answer is no, its not.

Heres why.

Immune responses are innate or acquired. Innate, or short-term immunity, occurs when immune cells that are the bodys first line of defence are activated against a pathogen like a virus or bacteria.

If the pathogen is able to cross the first line of defence, T-cells and B-cells are triggered into action. B-cells fight through secreted proteins called antibodies, specific to each pathogen. T-cells can be categorised into helper T-cells and killer T-cells. Helper T-cells help B-cells in making antibodies. Killer T-cells directly kill infected cells.

Once the battle is over, B-cells and T-cells develop memory and can recognise the invading pathogen next time. This is known as acquired or adaptive immunity, which triggers long-term protection.

What happens when you get reinfected? Memory B-cells dont just produce identical antibodies, they also produce antibody variants. These diverse set of antibodies form an elaborate security ring to fight SARS-CoV-2 variants.

Getting Covid and recovering (known as natural infection) doesnt appear to generate protection as robust as that generated after vaccination.

And the immune response generated post-infection and vaccination, known as hybrid immunity, is more potent than either natural infection or vaccination alone.

People who have had Covid and recovered and then been vaccinated against Covid have more diverse and high-quality memory B-cell responses than people whove just been vaccinated.

Studies indicate mRNA vaccines generate a more potent immune response with previous infection, at least against some variants including Alpha and Beta.

And studies have shown that antibody levels were higher among those whod recovered from Covid and were subsequently vaccinated than those whod only had the infection.

Memory B-cells against the coronavirus have been reported to be five to ten times higher in people vaccinated post-infection than natural infection or vaccination alone.

Some reports have suggested people whove had Covid need only one dose of the vaccine. Clinical trials of approved vaccines didnt generate relevant data because people whod already had Covid were excluded from phase 3 trials.

One study from June showed people with previous exposure to SARS-CoV-2 tended to mount powerful immune responses to a single mRNA shot. They didnt gain much benefit from a second jab.

A single dose of an mRNA vaccine after infection achieves similar levels of antibodies against the spike proteins receptor binding domain (which allows the virus to attach to our cells) compared to double doses of vaccination in people never exposed to SARS-CoV-2.

We need more studies to fully understand how long memory B-cell and T-cell responses will last in both groups.

Also, a single dose strategy has only been studied for mRNA-based vaccines. More data is required to understand whether one jab post-infection would be effective for all the vaccines.

At this stage, its still good to have both doses of a Covid vaccine after recovering from Covid.

The development of new vaccines must keep pace with the evolution of the coronavirus.

At least one variant seems to have evolved enough to overtake others, Delta, which is about 60% more transmissible than the Alpha variant. Delta is moderately resistant to vaccines, meaning it can reduce how well the vaccines work, particularly in people whove only had one dose.

Theres no data available yet about how effective a single jab is for people who were previously infected with Delta and recovered.

The most important thing you can do to protect yourself from Delta is to get fully vaccinated.

According to a Public Health England report, one dose of Pfizer offered only about 33% protection against symptomatic disease with Delta, but two doses was 88% effective.

Two doses was also 96% effective against hospitalisation from Delta. The AstraZeneca vaccine was 92% effective against hospitalisation from Delta after two doses.

A few vaccine manufacturers, including Pfizer, are now planning to use a potential third dose as a booster to combat the Delta variant.

Sunit K. Singh, Professor of Molecular Immunology and Virology, Institute of Medical Sciences, Banaras Hindu University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Researchers uncover way to harness the power of immunotherapy for advanced prostate cancer – Michigan Medicine

Wednesday, August 4th, 2021

Its a scientific riddle tangled up in a complex web. How do you turn an immune cold cancer into one that responds to immunotherapy?

Researchers led by the University of Michigan Rogel Cancer Center started with a simple thread: an inhibitor that showed promise against metastatic castration-resistant prostate cancer cells. This is the most challenging type of prostate cancer advanced disease that has become resistant to hormone-based treatment.

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From there, they continued to untangle the web to discover multiple levels of cellular processes that were preventing the immune system from mounting a response. Break past them with this inhibitor and suddenly whats considered an immune cold tumor turns red hot.

Immunotherapy has dramatically improved outcomes for some types of cancer. But prostate cancers are typically immune cold, which means these patients have benefited little from immunotherapies. Finding a way to rev up the immune response would create tremendous opportunity to improve patient outcomes, said Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine. Chinnaiyan is senior author of the paper published in Nature Cancer.

Researchers started by screening a library of 167 inhibitors against prostate cancer cells. They found one, ESK981, had the most impact.

ESK981 is a class of drugs called multi-tyrosine kinase inhibitors, which are designed to hit multiple targets. This means it functions like a combination therapy, able to block cancer on more than one front. It was originally developed to check blood vessel growth and has already been tested in phase 1 clinical trials, which found it to be safe and well-tolerated.

In cell lines and mice with metastatic castration-resistant prostate cancer, researchers found ESK981 inhibited tumor growth.

SEE ALSO: New Connections Reveal How Cancer Evades the Immune System

The response was intriguing, but we wanted to understand the mechanism at play with ESK981 in prostate cancer cells, Chinnaiyan said.

They discovered several cellular processes were occurring. First was the role of a type of cell death called autophagy. The authors surprisingly found that ESK981 was a potent inhibitor of autophagy in tumor cells. This caused the cancer cells to produce a protein called CXCL10, which led to recruitment of immune T cells to the tumor.

But there was one more layer to go. Ultimately, they traced it back to PIKfyve, a type of protein called a lipid kinase. The authors discovered that ESK981 directly targets PIKfyve, affecting these multiple processes involved in metabolism and cell death.

The researchers confirmed this by knocking down PIKfyve in cell lines and mice. They saw the same processes occur: tumors stopped growing, autophagy was controlled and more T cells were recruited to the tumor. When they added an immune checkpoint inhibitor to the PIKfyve knockdown, the impact was even greater, significantly reducing tumors.

Overcoming resistance to immunotherapy is an urgent need in prostate cancer. PIKfyve is a promising target, especially combined with an immune checkpoint inhibitor. This combination has potential to extend the benefit of immunotherapy to patients whose tumors have previously not responded, Chinnaiyan said.

Based on these findings, researchers have begun phase 2 clinical trials using ESK981 alone or in combination with the immunotherapy nivolumab for metastatic castration-resistant prostate cancer.

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Additional authors includeYuanyuan Qiao, Jae Eun Choi, Jean C. Tien, Stephanie A. Simko, Thekkelnaycke Rajendiran, Josh N. Vo, Andrew D. Delekta, Lisha Wang, Lanbo Xiao, Nathan B. Hodge, Parth Desai, Sergio Mendoza, Kristin Juckette, Alice Xu, Tanu Soni, Fengyun Su, Rui Wang, Xuhong Cao, Jiali Yu, Ilona Kryczek, Xiao-Ming Wang, Xiaoju Wang, Javed Siddiqui, Zhen Wang, Amelie Bernard, Ester Fernandez-Salas, Nora M. Navone, Stephanie J. Ellison, Ke Ding, Eeva-Liisa Eskelinen, Elisabeth I. Heath, Daniel J. Klionsky, Weiping Zou

Funding for this work comes from the Prostate Cancer Foundation Challenge Award, National Cancer Institute Prostate SPORE Grant P50CA186786, Department of Defense grant PC130151P1, National Institutes of Health grant GM131919. In addition, individual researchers are supported by NCI grant R35CA231996, Howard Hughes Medical Institute, A. Alfred Taubman Institute, American Cancer Society, PCF Young Investigator Awards, DoD Postdoctoral Award W81XWH-16-1-0195, and the Academy of Finland.

Disclosure: The University of Michigan has filed a disclosure on the findings based on this study. Chinnaiyan and Qiao are named as co-inventors. Esanik Therapeutics Inc. licensed ESK981 from Teva Pharmaceuticals. Chinnaiyan is a co-founder and serves on the scientific advisory board of Esanik Therapeutics Inc. Esanik Therapeutics or Teva Pharmaceuticals were not involved in the design or approval of this study, nor was this study funded by them.

Paper cited: Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer, Nature Cancer. DOI: 10.1038/s43018-021-00237-1

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‘I may have to start hibernating again’: Immunocompromised 27-year-old on Delta variant and booster shots – KCRW

Wednesday, August 4th, 2021

The U.S. is reporting more than 100,000 new COVID-19 cases a day numbers not seen since February when most people couldnt get vaccinated. As a result, on Monday, seven Bay Area counties reimposed indoor masking requirements, joining LA, Sacramento and Yolo counties. And employers are reevaluating whether back-to-the-office-after-Labor Day plans are realistic anymore.

The spread of the Delta variant is even more nerve-wracking for people with weakened immune systems, who were left out of initial vaccine trials. Because of that, its unclear how well the vaccine protects immunocompromised patients.

One of those immunocompromised patients is Trevor Achilles, a 27-year-old resident of Charlottesville, Virginia. After undergoing a kidney transplant 12 years ago, hes had to take immunosuppressive drugs to ensure his body doesnt reject the kidney.

He says the last 17 months have felt like hell. He was laid off during the early days of the pandemic and often found himself stuck.

I couldn't really see friends, I couldn't really go to the gym, or do anything else that I used to do before the pandemic. And so it was very taxing on me mentally and physically. I gained a lot of weight. And I was just sitting around, and getting depressed, watching all the horrible news. It was not fun.

Earlier this year, Achilles was vaccinated. When he was tested for antibodies, it turned out he didnt have any. Achilles says thats due to the nature of immunosuppressive drugs they protect his kidneys but fight off anything else that enters his body.

I got the flu before the pandemic began, and I was knocked out flat practically. And when I get sick, I tend to get sicker than most. And so I'm particularly vulnerable to getting something like COVID. And unfortunately, that pertains to the [COVID vaccine] shots as well, because my body just won't accept any kind of foreign interference.

Achilles lack of antibodies doesnt surprise Ghady Haidar, M.D from the University of Pittsburgh Medical Center. He looks at how infectious diseases can affect transplant patients. Most recently, Haidar has focused on how people with cancer, organ transplants, and autoimmune diseases respond to the COVID vaccines.

Vaccines work by triggering your immune system to respond to something. When you're taking medicines that work by suppressing the immune system, it just makes sense that vaccines aren't going to work as well, Haidar tells KCRW. This isn't unique to just COVID-19. This is true for every single vaccine that's out there.

Haidar recently led a study examining antibody responses in immunocompromised patients. It found that about 37% of organ transplant recipients produced antibodies. Thats compared to 94% of patients with well-treated HIV and about 80% of patients with blood cancer and autoimmune diseases.

He says the wide-ranging results are indicative of how certain conditions and their treatments can impact the body.

For example: A person getting chemotherapy for cancer, their immune system is not the same as someone getting, let's say, a TNF [tumor necrosis factor] inhibitor for their Crohns disease. And it's not the same as someone who just had a lung transplant a month ago. And that's not the same as someone who had a liver transplant 20 years ago.

At the recommendation of his doctor, Achilles received a third COVID vaccine in hopes that it would help him develop antibodies.

[My doctors] first goal is to keep me alive and healthy and safe. And she knows all about COVID and how it's impacting those of us who are immunocompromised, and she was really worried about me. And she figured that it'd be better to try to get some protection as opposed to having no protection at all, Achilles says. I just felt like it was the right thing to do, the natural thing to do. And I'm just hoping and praying this third shot will give me the antibodies that I need.

Haidar says other countries, including France and Germany, have started to distribute booster shots. In the U.S. however, vaccine regulators are waiting for more clinical trials and data in order to make a decision.

In the meantime, Achilles says hes laying low to protect himself from the new Delta variant.

He adds, I may have to start hibernating again, so to speak. I'm just really concerned about the Delta variants because it's much more contagious. I'm willing to do anything and everything to protect myself and my family.

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Study Pairs Two Forms of Immunotherapy in Patients with Advanced Kidney Cancer | Dana-Farber – Dana-Farber Cancer Institute

Wednesday, August 4th, 2021

Published: August 2, 2021

Stymied and disoriented. Thats one way to describe the state of the immune system in some patients with cancer. T cells revved up to attack tumors are turned into an army of loiterers. Cells keenly attuned to signals of infection or disease fail to pick up the faint notes of cancer.

A clinical trial led by Dana-Farber researchers is addressing both of these issues in patients who have undergone surgery for kidney cancer but have a high risk of recurrence. Patients in the trial receive the latest generation of NeoVax, a personalized vaccine made from tiny bits of each patients tumor cells. They also are treated with a local injection of an immune checkpoint inhibitor, which liberates a specific group of T cells to take up an assault on tumor cells.

In the words of David Braun, MD, PhD, the principal investigator of the trial (with Toni Choueiri, MD, and Patrick Ott, MD, PhD), the checkpoint inhibitor releases the brakes on the immune response while the personalized vaccine makes it possible to steer the immune system specifically to a patients tumor.

The dual approach seeks to improve on the results achieved by either treatment alone. Checkpoint inhibitors, which have transformed the treatment of some cancers, have had little success against others. NeoVax, developed by Dana-Farbers Catherine Wu, MD, and her colleagues, has performed well in clinical trials, but its potential has only begun to be explored.

Patients with advanced kidney cancer are in need of better treatments to prevent the return of their disease and particularly stand to benefit from this combination, Braun remarks.

Even after surgery to remove the kidney, where a patient might have no evidence of disease on imaging, patients with stage III or IV cancer are at high risk of recurrence. Right now, the tools we have to lower that risk are limited.

Richard Boylan is one of those who, in the absence of the trial, would have faced a dearth of options to prevent his cancer from coming back. Diagnosed with stage III kidney cancer in mid-2019, Boylan, 67, learned about the trial from his local surgeon.

He explained that the trial would be integrated with the surgery, says Boylan, of Holliston, Mass. When the tumor was removed in October, it was sent to Dana-Farber for analysis.

At the Institute, technicians sequenced the DNA in the tumor and in a sample of Boylans blood to identify the genetic changes that distinguished the tumor cells from the bodys normal cells. Specialists used bioinformatics to predict which of these changes, or mutations, were most likely to trigger an immune response.

We pick the top 20 targets and make millions of copies of each one in the form of peptides, short chains of amino acids, that stimulate the immune system, Braun explains. We then inject these peptides, which constitute the NeoVax vaccine, into patients.

The peptides are paired with low doses of a local injection of a checkpoint inhibitor. The hope is we can lift the brakes just enough to stir the immune response without producing adverse effects, Braun notes.

In February and June of 2020, Boylan underwent leukapheresis procedures, which separate out white blood cells from the rest of the blood. The first one was done prior to treatment with NeoVax, the second one after. Each sample of white blood cells would be mixed with tumor cells in what Boylan calls a laboratory cage match to see if the cells in the second sample, enriched with tumor cell peptides, mount a fiercer attack on the cancer than cells in the first sample.

The trial itself involved a lot of shots, a lot of needles, over an extended period, Boylan remarks, adding, I am not a big fan of needles.

At each treatment session, Boylan received three shots in each arm and each leg. Two of those three shots consisted of the peptides, the other was an immune stimulant. (The trial involves targeting many different mutations or neoantigens; hence the injections in each limb.)

The only noteworthy side effect, Boylan says, came when he was receiving the vaccine every week.

Some of them would knock me back for at least 24 hours it felt like having the flu. But, honestly, the side effects from my most recent shingles shot were worse than those from the vaccine.

The trial is supported by Gateway for Cancer Research, and the laboratory-based research is supported by the Department of Defense Congressionally-Directed Medical Research Program. As the trial is still underway, effectiveness of the regimen hasnt been analyzed, but Boylan has picked up some promising signs.

For some patients, theres a 40% risk of recurrence over an extended period of time, he says, but you can tell by the enthusiasm you hear in talking to the doctors how well the study is going.

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CD38 Expression Linked With Poor OS in Prostate Cancer – OncLive

Wednesday, August 4th, 2021

Results showed that in patients with metastatic castration-resistant prostate cancer (mCRPC), CD38 mRNA expression was significantly linked with upregulated immune-signaling pathways, plus interleukin (IL)-12, IL-23, and IL-27 signaling signatures, immunosuppressive adenosine signaling, and T-cell exhaustion signatures.

While CD38 was largely absent from tumor epithelial cells, it was often expressed in phenotypically diverse TIICs, such as B cells and myeloid cells. Moreover, CD38-positive TIIC density was associated with worse overall survival (OS) and increased with progression to castration-resistant prostate cancer (CRPC).

We believe that CD38 on the surface of immune cells is acting to dampen down the immune response. We have shown that the presence of this protein on immune cells within prostate tumors is a sign of worse survival outcomes and exhausted anticancer immune responses, said lead study author Johann de Bono, MD, MSc, PhD, FRCP, FMedSci, professor of experimental cancer medicine at The Institute of Cancer Research in London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust.2 It is now clear that CD38 has a role in prostate cancers growth and spreadsuggesting that targeting it with drugs, which already exist and are used in other cancers, could be a promising new approach to treatment.

OS for patients with mCRPC remains poor at 2 to 3 years, and improving outcomes remains dependent on overcoming immunosuppressive barriers in the prostate tumor microenvironment (TME). CD38 upregulation in TIICs has been observed in some gastrointestinal cancers, though not in prostate cancer; however, increasing data have shown evidence that CD38 expression plays and role in tumor immune evasion, and as such, could factor into disease progression in prostate cancer, and serve as an immunotherapeutic target.

In this study, investigators sought to determine the clinical impact of CD38 expression in patients with mCRPC as they progressed to evaluate the potential use of CD38-directed therapies for the treatment of mCRPC.

For this analysis, RNA-sequencing from 159 patients with mCRPC from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) project, as well as 171 samples from 63 patients at the Fred Hutchinson Cancer Research Center, were analyzed for CD38 expression. Samples were then immunohistochemically scored by a validated assay of 51 CRPC biopsies, and matching same-patient castration-sensitive prostate cancer (CSPC) biopsies.

Among these 51 patients, CSPC samples were taken from the prostate (n = 50) and lymph node (n = 1), while CRPC samples were taken from the lymph nodes (n = 30), bone (n = 12), soft tissue (n = 3), liver (n = 3), and prostate (n = 3). mCRPC samples were analyzed for associations between CD38 and other gene expression signatures, while differences in CD38-expressing TIIC densities in the CSPC and CRPC biopsies were evaluated using a negative binomial mixed model. Moreover, multiplex immunofluorescence evaluated CD38 expression.

Results showed that CD38 expression occurred in 35.8% of normal prostatic epithelial cells vs 7.7% of tumor epithelium cells (P < .001). Additionally, the rates of CD38 expression were similar between CSPC and CRPC biopsies, at 9.8% and 3.9%, respectively (P = .45).

In the CSPC samples analyzed, CD38-positive TIIC density was associated with worse OS outcomes from initial diagnosis (HR, 1.36; 95% CI, 1.08-1.70; P = .008). Additionally, high CD38-positive TIIC density, defined as more than 1.5 cells/mm2, was associated with shorter OS from the time of initial diagnosis vs those with low CD38-positive TIIC density (HR, 1.99; 95% CI, 1.09-3.62; P = .02).

Results were similar in the CRPC samples, with CD38-positive TIIC density leading to worse OS outcomes from both the time of biopsy (HR, 1.20; 95% CI, 1.00-1.42; P = .04) and the time of CRPC diagnosis (HR, 1.40; 95% CI, 1.14-1.70; P < .001). Moreover, high CD38-positive TIIC density in these samples was also associated with shorter OS from the time of diagnosis vs low CD38+ TIIC density (HR, 2.24; 95% CI, 1.15-4.00; P = .02).

Additionally, results from a multivariable analysis showed that the CD38-expressing immune cell density seen in CSPC samples lead to worse OS from the time of prostate cancer diagnosis (HR, 1.42; 95% CI, 1.08-1.87; P = .01).

As cancers develop, they often evolve the ability to evade the immune system so they can keep growing and spreading without being attacked. This new study suggests that in prostate cancer, tumors can suppress the immune system via the CD38 molecule on the surface of immune cells, said Paul Workman, FRS, FRSC, FMedSci, chief executive of The Institute of Cancer Research in London. The findings are exciting and open up a whole new potential approach to treating prostate cancer using immunotherapyan approach that is now being tested in clinical trials which have the potential to show real benefit for patients.

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Tyson Foods will require its 120,000 U.S. workforce to get vaccinated – CNBC

Wednesday, August 4th, 2021

The exterior of a Tyson Fresh Meats plant is seen on May 1, 2020 in Wallula, Washington. Over 150 workers at the plant have tested positive for COVID-19, according to local health officials.

David Ryder | Getty Images

Meatpacker Tyson Foods announced Tuesday that it will require its 120,000 U.S. employees to be vaccinated fully this year and will pay them a $200 bonus to do so.

The company said 56,000 U.S. employees have been vaccinated. Office workers face a deadline of Oct. 1 to be vaccinated fully, while plant employees have until Nov. 1.

The Centers for Disease Control and Prevention said Monday that the seven-day average of new infections surpassed last summer's peak, before the country had access to vaccines. U.S. Covid cases, based on a seven-day moving average, reached 72,790 on Friday, according to the agency's data. The delta variant is fueling the surge in cases, especially in areas with low vaccination rates.

"It is abundantly clear that getting vaccinated is the single most effective thing we can do to protect ourselves, our families and our communities," CEO Donnie King said in a memo to employees.

Tyson plans to give front-line workers who get vaccinated the $200 bonus, in addition to the current policy of providing up to four hours of pay for getting inoculated outside of work or through an external provider. The extra pay, as well as the deadline, are subject to talks with unions who represent those employees.

The United Food and Commercial Workers, which represents 24,000 Tyson workers, said that it will be meeting with Tyson in the coming weeks to discuss the mandate and make sure that the workers' rights are protected. The union said that it encourages workers to get vaccinated but noted several concerns about the company's vaccine mandate.

"We believe the FDA must provide full approval of the vaccines and help address some of the questions and concerns that workers have," UFCW International President Marc Perrone said in a statement to CNBC. "Additionally, employers should provide paid time off so that their essential workers can receive the vaccine without having to sacrifice their pay, and can rest as needed while their body adjusts to the vaccine and strengthens their immune system to fight off the virus."

Tyson said it will allow exceptions to the vaccine mandate for medical or religious reasons.

Throughout the pandemic, many meat and poultry processing facilities have been forced to close temporarily after outbreaks of Covid-19 swept through their workforce. Conditions in the plants require employees to work closely together for hours at a time, making social distancing nearly impossible. Group housing and shared transportation to and from work also increase contact among workers.

At least 132 meatpacking workers who belonged to the UFCW have died after contracting Covid according to the union.

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Disparate regulation of IMD signaling drives sex differences in infection pathology in Drosophila melanogaster – pnas.org

Wednesday, August 4th, 2021

Significance

Sex differences in infection outcome are a widely observed phenomenon. While it is known that biological sex can influence an animals response to infection, the mechanisms through which these differences emerge are less clear. Here, we describe a mechanism through which heightened regulation of the IMD signaling pathway by femalebut not maleDrosophila melanogaster reduces the cost of immune activity at the expense of resistance to bacterial infection. Through the masculinization of the main organ responsible for antimicrobial peptide activity in the fly (fat body), this work demonstrates that this heightened immune regulation is mediated by sex-determining pathways.

Male and female animals exhibit differences in infection outcomes. One possible source of sexually dimorphic immunity is the sex-specific costs of immune activity or pathology, but little is known about the independent effects of immune- versus microbe-induced pathology and whether these may differ for the sexes. Here, by measuring metabolic and physiological outputs in Drosophila melanogaster with wild-type and mutant immune responses, we test whether the sexes are differentially impacted by these various sources of pathology and identify a critical regulator of this difference. We find that the sexes exhibit differential immune activity but similar bacteria-derived metabolic pathology. We show that female-specific immune-inducible expression of PGRP-LB, a negative regulator of the immune deficiency (IMD) pathway, enables females to reduce immune activity in response to reductions in bacterial numbers. In the absence of PGRP-LB, females are more resistant to infection, confirming the functional importance of this regulation and suggesting that female-biased immune restriction comes at a cost.

Biological sex can influence an animals response to infection, with females often mounting stronger innate and adaptive immune responses compared to males. Across multiple taxa, the sexes exhibit differing incidences of infection, pathogen loads, pathogen-derived virulence, and immune efficacy (18). In humans, the greater responsiveness of the female immune response can confer rapid pathogen clearance, reduced mortality rates, and greater efficacy of vaccines; however, it also thought to be responsible for the increased incidence of inflammatory and autoimmune disease in women (3, 9, 10). Thus, females appear to trade-off the rapid and efficient clearance of foreign bodies, with the risk of doing self-harm, either due to autoimmunity or immunopathology. Consequently, sex-specific infection outcomes could be driven by differences between the sexes in the risks of autoimmunity, immunopathology, virulence (pathogen-induced harm), or trade-offs between immunity and other important traits.

The origins of infection-induced pathology and the mechanisms employed by hosts to limit pathology are key issues in understanding this difference between the sexes. Infection pathology can result from direct interactions between host and pathogen or can be driven indirectly. Direct pathology is caused by the pathogen itself and its products and can be produced by many effects; pathogen- or pathogen effectordriven damage to host tissue (11, 12) is the most obvious of these, but other direct pathological processes include competition with the host for access to resources (1315). Indirect pathology, in contrast, is caused not by the pathogen itself but by some aspect of the host response to the pathogen and is most often conceived as pathology caused by immune effectors; other indirect pathologies come in the form of immune trade-offs, where immune activation leads to the reallocation of host resources from other processes, such as longevity, reproduction, competitive ability, and development (5, 1623).

Differences in infection outcomes between hosts can result from differences in the ability of the host to clear the pathogen (resistance mechanisms) or from differences in sensitivity to direct or indirect pathology (tolerance mechanisms). In any given infection, the survival and continued health of the host will be the product of a complex interaction of host and pathogen genotype as well as other factors. It is unclear whether the well-documented effects of host sex on infection outcome in general primarily originate in changes in resistance to the infectious agent or in tolerance of direct or indirect pathology.

To distinguish these effects, we used the fruit fly Drosophila melanogaster and consider the response of w1118 control and immunocompromised flies to infection with the bacterium Escherichia coli. Unlike mammals, D. melanogaster lacks an adaptive immune response, instead, flies have a well-developed innate immune response consisting of both cellular and humoral components. The humoral response of D. melanogaster involves the inducible production of circulating factorsprimarily antimicrobial peptides (AMPs)that are directly microbicidal. Though infection with E. coli is nonlethal and efficiently controlled by the immune response of w1118 flies, E. coli infection cannot be controlled in immunocompromised flies (24). Therefore, using this system, we sought to distinguish between pathology resulting from the immune response and pathology resulting from the microbe. We test whether the sexes are differentially impacted by these two sources of pathology using multiple metabolic and physiological measures as readouts. We show that females reduce the cost of immune activity via strict regulation of the immune deficiency (IMD) pathway and that this comes at the cost of bacterial clearance.

To determine whether male and female flies exhibited a difference in their ability to defend against nonpathogenic gram-negative bacterial infection, we first measured survival and bacterial numbers after infection with E. coli of w1118 flies (henceforth referred to as wild-type because they have an intact immune response). Previous work has found that D. melanogaster infected with E. coli either eliminate the bacteria or maintain them at low levels at no obvious cost to the host (25, 26). As expected, we did not find a strong effect of infection with live or dead (heat killed) E. coli on the lifespan of wild-type flies (Fig. 1A and SI Appendix, Fig. S1A and Table S1). However, when we compared bacterial numbers between infected males and females, we found a clear trend toward greater numbers of surviving bacteria in females, which was significantly different at 3, 4, and 6 h following infection (Fig. 1B).

Sex-specific outcomes of E. coli infection. Representation in all plots: males, black; females, blue. (A) Survival of E. coliinfected wild-type flies. E. coliinfected flies are indicated by solid lines. Uninfected and PBS controls are indicated by long and short dashed lines, respectively. Flies had an average median survival across all treatments of 21.5 and 18.5 d for females and males, respectively (Coxph: degrees of freedom [df] = 7, n = 396, Wald test = 43.75, P = 2 107). There was no effect of treatment on survival in either sex. Survivals were performed at least twice, each repeat included 20 to 40 flies/treatment. (B) Bacterial quantification in wild-type flies. Females had more bacteria than males at 3 (Wilcoxon: W = 120, P = 0.019, n = 25), 4 (Students t test = 2.71, P = 0.013, n = 25), and 6 h (Wilcoxon: W = 148, P = 1.1 104, n = 25) postinjection. Markers indicate means, and bars represent SE. Statistical significance: *P < 0.05; ***P < 0.001. Quantifications were performed twice, each repeat included six to eight biological replicates consisting of one fly each. (C and D) AMP transcript levels 3 (C) and 6 h (D) postinfection in wild-type flies. Expression is shown relative to uninfected flies of the same sex. On average, infected males had AMP transcript levels 16 greater than females (Mtk-25x; DptA-19x; Def-3x; CecA1-0.65x; Drs-25x; AttaA-19x; Dro-23x). Solid lines represent infection with E. coli, while dotted lines are PBS injected. The area contained within the innermost heptagon represents induction levels falling between 1 and 10 times that of the uninfected controls. The middle and outer heptagons represent 100- and 1,000-fold induction, respectively. These data are also shown, represented differently, in SI Appendix, Fig. S1. AMP assays were performed two to four times, each repeat included three or four biological replicates/treatment consisting of three flies each.

Defense against E. coli infection is expected to depend primarily on the activity of the IMD signaling pathway and its AMP target genes (27, 28). The fact that males and females exhibited differences in bacterial numbers led us to examine AMP mRNA expression 3 and 6 h after infection; these times were chosen because 3 h was not long after the bulk of bacterial killing had been achieved, while 6 h is the reported peak of Diptericin inductiona canonical read-out of imd activityin wild-type animals (29). At 3 h after infection, male and female flies exhibited broadly similar levels of AMP transcripts (Fig. 1C and SI Appendix, Fig. S1B). However, by 6 h after infection, AMP expression was significantly reduced in female flies relative to males, despite females having higher bacterial numbers (Fig. 1D and SI Appendix, Fig. S1C). Importantly, AMP levels were notably greater in infected females 3 h following injection than they were at 6 h, while male levels were unchanged, possibly as a result of females being more responsive to bacterial load as a cue to shut down immune activity.

The fact that we found the regulation of IMD signaling was different between the sexes led us to look more closely at the sex-specific consequences of the loss of imd function during E. coli infection. We infected imd mutants with E. coli and found that both sexes had significantly reduced survival when infected with E. coli compared to their phosphate-buffered saline (PBS)-injected and uninfected controls; infected imd males had a median survival only 60% that of imd females (Fig. 2A and SI Appendix, Fig. S2A). We then injected imd mutants with latex beads to inhibit their ability to phagocytose bacteria (30), resulting in flies with both phagocytosis and AMP activity inhibited; inhibiting the phagocytic response with latex beads did not affect survival in either sex (SI Appendix, Fig. S2B), further supporting the idea that AMP activity plays the primary role in this infection. When we examined bacterial loads in male and female imd mutants, we found that both sexes carried similar numbers of bacteria at all but one measured time, indicating that the difference in survival between male and female animals reflected different levels of infection tolerance (Fig. 2B). The fact that this differential tolerance effect was revealed only in imd mutants implied that it was a consequence of different components of nonIMD pathway immune activation and that the secondary immune response pathways revealed by imd mutation were more damaging to males, possibly because of quantitative differences in their activation between the sexes.

Sex-specific outcomes of E. coli infection in imd flies. Representation in all plots: males, black; females, blue. (A) Survival of E. coliinfected flies. Infected flies are indicated by solid lines. Median survival of E. coliinfected imd flies was 34 and 17 h for females and males, respectively (Coxph: df = 9, n = 255, Wald test = 126.2, P < 2 1016). Survivals were performed at least twice, each repeat included 20 to 40 flies/treatment. Uninfected and PBS controls are here excluded for better visualization of the sex difference in survival. Survival of uninfected and wounded controls did not differ between the sexes during the assayed time (Log-Rank pairwise test: uninfected: P = 0.634; PBS: P = 0.198). Full survival including uninfected and PBS and controls shown in SI Appendix, Fig. S2. (B) Bacterial quantification in imd mutant flies. With the exception of 5 h postinfection when males had significantly more bacteria than females (Wilcoxon: W = 28.5, P = 4.4 103, n = 26), imd flies exhibited no difference in bacterial number between the sexes. Wild-type quantifications performed in tandem with imd flies are indicated in gray; note that this represents the same data shown in Fig. 1, and is repeated here to enable easy comparison. Markers indicate means, and bars represent SE. Statistical significance: **P < 0.01 Quantifications were performed twice, each repeat included six to eight biological replicates consisting of one fly each. (C) AMP transcript levels 6 h postinfection in imd mutant flies. Expression is shown relative to uninfected flies of the same genotype/sex. Solid lines represent infection with E. coli, while dotted lines are PBS injected. The area contained within the innermost heptagon represents induction levels falling between 1 and 10 times that of the uninfected controls. The middle and outer heptagons represent 100- and 1,000-fold induction, respectively. These data are also shown, represented differently, in SI Appendix, Fig. S2. AMP assays were performed two to four times, each repeat included three or four biological replicates/treatment consisting of three flies each.

We tested this possibility by assaying AMP induction in imd mutants infected with E. coli. Females exhibited no response at all, while males exhibited a residual 10- to 100-fold induction of most AMPs (Fig. 2C and SI Appendix, Fig. S2). This level of expression was clearly insufficient for antimicrobial activity, as the sexes exhibited similar bacterial numbers but was potentially enough to cause pathology in imd mutant males.

Because resources are finite, individuals must manage investments in multiple biological processes. The ability to draw on metabolic reserves of triglyceride or glycogen allows animals to run temporary metabolic deficits in response to unexpected costs (e.g., immunity). We hypothesized that the sex differences we observed in immune activity and tolerance of infection in wild-type and imd mutant flies, respectively, might also be reflected in differences in the metabolic cost of infection. To test this, we assayed levels of free sugar (glucose and trehalose), stored carbohydrate (glycogen), stored triglyceride, and respiration in wild-type and imd flies. Previous studies in D. melanogaster found that lethal bacterial infections can lead to hyperglycemia, as well as a reduction in triglyceride and glycogen stores, but these metabolites had not been examined during acute infection with nonpathogens (3133).

We found that 6 h postinfection with E. coli, wild-type flies had significantly less stored triglyceride than their PBS controls; this effect was independent of sex (Fig. 3A and SI Appendix, Table S2). Importantly, infection with heat-killed E. coli did not deplete triglyceride, indicating that this effect is dependent on the presence of live bacteria and not merely on general immune activation. Wild-type males had significantly less circulating sugar but more glycogen than females, but neither of these was changed by infection. Respiration was unaffected by infection status in wild-type flies (SI Appendix, Fig. S3). imd mutants exhibited a somewhat different pattern to wild type, as there was no effect of infection on free sugar levels nor glycogen in either sex (Fig. 3B). As in wild-type flies, both male and female imd mutants exhibited significant reduction in triglyceride resulting from infection, and this effect was notably stronger in males (26 versus 13% less than PBS controls for males and females, respectively; Fig. 3B and SI Appendix, Table S2). This fit with our observation that imd mutant males exhibited a stronger (though clearly ineffective) immune response to E. coli infection than imd mutant females, as a possible cause for greater triglyceride depletion in males could be increased demands resulting from immune activity. Alternatively, males could be diverting resources into other, nonimmune-related activities, such as foraging or reproduction (34, 35).

No sex difference in metabolic pathology of E. coli infection in wild-type and imd flies. Triglyceride and carbohydrate levels in live and heat-killed E. coliinfected flies. Data shown are quantities normalized to the mean of uninfected sex-matched controls. (A) In wild type, we employed an analysis of variance (AOV) there was an effect of sex on circulating sugar (AOV: df = 1, n = 67, F = 14.7, P = 2.7 104) and glycogen levels (AOV: df = 1, n = 59, F = 6.15, P = 0.016) with males having less circulating sugar but more glycogen stores than females. There was also an effect of infection status on triglyceride levels, such that E. coli infection led to triglyceride loss (AOV: df = 2, n = 74, F = 5.73, P = 4.8 102). There was no interaction between sex and infection on triglyceride loss. (B) imd flies showed no effect of sex nor infection status on circulating sugar and glycogen levels. There was no effect of sex on triglyceride levels, but there was an overall effect of both treatment (AOV: df = 1, n = 49, F = 44.971, P = 2.8 108) and the interaction between sex and treatment on triglycerides; E. coli infection led to triglyceride depletion in both sexes, relative to their PBS controls (AOV: df = 1, n = 49, F = 7.417, P = 9.2 103; male PBS-male [PBS-M] E. coli, P adjusted = 4.0 107; female PBS-female [PBS-F] E. coli P adjusted = 1.01 102). Bars indicate SE. Letters indicate statistical groupings. Full statistics including nonsignificant results can be found in SI Appendix, Table S2. All assays were performed two or three times, each repeat included four biological replicates/treatment consisting of three (carbohydrates) or eight (triglycerides) flies each.

Because animals spend significant energy on reproduction, and reproductive effort is likely to restrict or trade-off with immunity (36), we assayed reproductive output during infection. We placed infected flies in tubes with flies of the opposite sex and competitors of the same sex but of a different genotype (Dh44[3xP3-DsRed]). We allowed flies to mate for 12 h and then discarded adults. Offspring resulting from matings with competitors were easily identifiable by their red-fluorescent eyes. Both wild-type and imd males were less likely to have a successful mating interaction than their female counterparts, but neither sex showed an effect of infection on mating success or the number of offspring produced (SI Appendix, Fig. S4). These findings demonstrate that despite observing metabolic shifts and sex-specific AMP induction and pathology (bacterial load), reproductive output is unaffected in the short term by E. coli infection.

We have shown that male and female flies exhibit clear differences in the dynamics of the transcriptional response to E. coli infection, presumably due to distinct mechanisms of immune regulation and that in flies lacking the IMD pathway, male animals exhibit distinctly greater responses to infection in terms of gene expression and triglyceride depletion and die more rapidly than females. We wished to gain some mechanistic insight into these differences between the sexes, so we analyzed the expression of known negative regulators of IMD signaling in male and female flies. We expected that negative regulators responsible for the effects we observed on AMP expression should be more inducible in females.

Several negative regulators of IMD pathway activity have been described (3740). We assayed several of these regulators for increased infection inducibility in female flies relative to males (SI Appendix, Fig. S5A). Two negative regulatorsPGRP-LB and RYBPwere expressed at higher levels specifically in E. coliinfected females 3 h postinfection (Fig. 4 A and B). A more-detailed analysis of the time course of expression of PGRP-LB and RYBP revealed that both were up-regulated as early as 1 h after infection in females, and both showed continuing strong expression 3 h after infection, especially in females (Fig. 4 A and B and SI Appendix, Fig. S5B). However, by 6 h after infection, PGRP-LB expression had returned to near normal in both males and females, while RYBP expression was now induced in males to the same high level seen from 1 h in females. This difference in the regulatory timing of the IMD pathway can be seen when we compare AMP expression at 3 and 6 h in each sex (Fig. 4 C and D).

Sex-specific temporal regulation of imd during E. coli infection wild-type flies. Representation in all plots: males, black; females, blue. (A and B) Expression of PGRP-LB (A) and RYBP (B) 1, 3, and 6 h after infection in male and female flies. Plotted values are relative to the uninfected controls. Solid lines represent infection with E. coli, while dotted lines represent PBS injection. These data are also shown, represented differently, in SI Appendix, Fig. S5B. (C and D) AMP transcript levels in females (C) and males (D) 3 and 6 h after infection. Expression is shown relative to uninfected flies of the same genotype/sex. Solid lines represent infection with E. coli, while lines dotted are PBS injected. Data collected at 6 h are indicated in red. The area contained within the innermost heptagon represents induction levels falling between 1 and 10 times that of the uninfected controls (down-regulation was not observed in any of the tested genes). The middle and outer heptagons represent 100- and 1,000-fold induction, respectively. AMP assays were performed two to four times, each repeat included three or four biological replicates/treatment consisting of three flies each.

PGRP-LB is an amidase that degrades the DAP-type peptidoglycan of gram-negative bacteria, dampening activation of the IMD pathway by degrading the activating ligand (40). In contrast, RYBP inhibits IMD pathway activity by promoting proteasomal degradation of the pathways NF-B transcription factor, Relish (38). PGRP-LB reduces pathway activity by degrading free peptidoglycanthat is, it reduces pathway activity only when the immune response has been effective in killing bacteria; it was thus particularly interesting because its activation upon infection renders the IMD pathway responsive to its own success. Peptidoglycan-degrading activity also could regulate IMD-independent immune responses, which could explain the sex differences we observed in immune activity, metabolic impact, and infection pathology in imd mutants. We thus decided to analyze immune function in male and female PGRP-LB mutants.

To test whether PGRP-LB activity was responsible for the sex difference in immune function, we infected male and female PGRP-LB null mutants with E. coli and measured AMP expression, bacterial numbers, and survival of the host. In the absence of PGRP-LB, the male-biased AMP expression observed 6 h following infection with E. coli in wild-type flies was abolished (Fig. 5A and SI Appendix, Fig. S6A). PGRP-LB mutants had fewer bacteria than wild type at all time points assayed (1, 3, and 6 h; Fig. 5B). As in wild-type flies, PGRP-LB mutants of both sexes drastically reduced bacterial load within the first 2 h postinfection, at which time bacterial numbers effectively plateaued. However, in contrast to what we saw in wild-type flies, PGRP-LB females did not carry higher bacterial loads than males at any point throughout the 6-h period assayed (Fig. 5B), confirming our supposition that wild-type females down-regulate AMP activity at a cost of resistance, and indicating that sex-specific PGRP-LB induction has important functional consequences for the realized immune response.

PGRP-LB males and females exhibit parallel metabolic shifts during infection. Representation in all plots: males, black; females, blue. (A) AMP expression is shown relative to uninfected flies of the same genotype/sex. Solid lines represent infection with E. coli, while dotted lines are PBS injected. The area contained within the innermost heptagon represents induction levels falling between 1 and 10 times that of the uninfected controls. The outer heptagon represents 100-fold induction. Assays were performed twice, each repeat included three to four biological replicates/treatment consisting of three flies each. These data are also shown, represented differently, in SI Appendix, Fig. S6A. (B) Bacterial load observed over the first 6 h of infection in PGRP-LB flies did not differ between the sexes. Wild-type quantifications were performed in tandem with PGRP-LB flies at select time points (1 , 3, and 6 h) and are indicated in gray. Wild-type flies had significantly more bacteria than PGRP-LB at all points measured (1 h: KruskalWallis = 24.8, P = 1.7 105, n = 79; 3 h KruskalWallis = 18.4, P = 3.7 104, n = 70; 6 h KruskalWallis = 30.7, P = 9.9 107, n = 55). Markers indicate means, and bars represent SE. Statistical significance: *P < 0.05; **P < 0.01; ***P < 0.001. Quantifications were performed two to four times, each repeat included five to eight biological replicates consisting of one fly each. (C) Infection had a significant effect on circulating sugar such that the amount of circulating sugar in E. coliinfected animals was lower than in PBS controls (AOV: df = 1, n = 32, F = 6.44, P = 1.7 102), whereas sex had no effect on circulating sugars, nor was there a significant interaction between the two. Similarly, E. coli infection led to marked reduction in stored glycogen (AOV: df = 1, n = 32, F = 9.41, P = 4.8 103), with no effect of sex, nor a significant interaction between sex and treatment. Neither infection status nor sex effected triglyceride levels. Large, filled markers indicate means, while smaller circles represent individual data points. Letters indicate statistical groupings. Bars indicate SE. All assays were performed twice, each repeat included four biological replicates/treatment consisting of three (carbohydrates) or eight (triglycerides) flies each. Full statistics including nonsignificant results can be found in SI Appendix, Table S3. (D) Survival of flies infected with E. coli indicated by solid lines. Uninfected and PBS controls are indicated by long and short dashed lines, respectively. E. coliinfected females had a median survival 58% greater than that of males (Female = 20.9 d, Male = 13.2 d; Coxph: df = 5, n = 484, Wald test = 119, P = 2.0 1016). Survivals were repeated thrice, each repeat included one or two biological replicates/treatment consisting of 20 flies each (note that data after day 21 represent two repeats). Full survival including uninfected wild-type controls is shown in SI Appendix, Fig. S7B. (E) PGRP-LB expression 3 h postinfection (p.i.) with E. coli in flies with tra knocked down in the fat body. Data are shown relative to uninfected flies of the same genotype/sex. Solid lines represent infection with E. coli, while dotted are PBS injected. Red and black tracings show tra knock down in the fat body and driver control, respectively. The area contained within the innermost heptagon represents induction levels falling between one and two times that of the uninfected controls. The outer heptagon represents eightfold induction. Assays were performed twice, each repeat included three to four biological replicates/treatment consisting of three flies each. These data are also shown, represented differently, in SI Appendix, Fig. S7C.

We next aimed to identify the effects of PGRP-LB on the physiological consequences of immune activationin particular, to explore the extent to which the metabolic consequences of acute infection are driven by host- or pathogen-derived activities. We predicted that if triglyceride loss observed in both sexes during E. coli infection in wild-type flies is driven entirely by pathogen-derived costs that the reduced bacterial load observed in infected PGRP-LB flies might be sufficient to abrogate triglyceride loss; conversely, if triglyceride loss were driven by IMD pathway activity, the prolonged IMD pathway activation observed in PGRP-LB mutants should result in greater loss of triglyceride than in wild-type animals. We found that in both male and female PGRP-LB flies, triglyceride levels were unaffected by E. coli infection, confirming that something other than IMD pathway activity causes triglyceride depletion in this infection. Infected PGRP-LB flies of both sexes had lower levels of circulating sugars and glycogen (Fig. 5C and SI Appendix, Table S3). This effect of infection on circulating and mobile energy observed in PGRP-LB flies may be indicative of the energy requirement of an unabated immune response.

The effect on overall lifespan was more complex: similar to what we observed in wild-type flies, independent of infection status, PGRP-LB females lived longer than males (Fig. 5D). Wounding had a significant impact on survival in females, with both PBS- and E. coliinjected animals having reduced survival (though the two treatments did not differ from each other). Because PGRP-LB should have little effect in the absence of peptidoglycan, the effect of sterile wounding in females was somewhat confusing; one possibility is that the previously documented effect of PGRP-LB on interaction with microbiota-derived peptidoglycan may have specific importance in the regulation of immune responses following sterile injury (41).

We wished to determine the roles of sex-specific regulatory factors and immune pathway activation in driving the female-specific PGRP-LB induction seen after E. coli infection. The gene transformer (tra) is part of the regulatory pathway responsible for female sex determination in D. melanogaster. Functional Tra protein is produced only in females and is necessary for most female-specific gene expression in somatic tissues and consequently for several sex-specific traits related to growth, metabolism, and aging pathologies (4245). Since E. coli peptidoglycan activates the IMD pathway, leading to the synthesis and secretion of AMPs by the fat body (24, 27, 46, 47), and PGRP-LB degrades peptidoglycan to prevent IMD pathway activation, we decided to knockdown tra in the fat body to test its requirement in sex-specific regulation of PGRP-LB. At 3 h after injection, PBS- and E. coliinfected females with tra knocked down (c564 > tra-IR) had reduced PGRP-LB expression relative to their genetic controls and males of the same treatment (Fig. 5E and SI Appendix, Table S5). As expected, tra knockdown in males had no effect on PGRP-LB expression. The IMD pathway is required for most E. coliinduced gene expression; we tested PGRP-LB expression in imd mutant flies and found that E. coli infection did not induce PGRP-LB expression in these animals (SI Appendix, Fig. S6B). These findings demonstrate that PGRP-LB expression is driven via combined inputs from tra and the IMD pathway, resulting in female-specific transcriptional induction of this regulator after infection.

Differences between males and females in immune activity and infection outcomes are pervasive throughout the animal kingdom. Here, we have explored the differences between male and female Drosophila in their response to a nonpathogenic gram-negative bacterial infection. Though both males and females could control this infection at the cost of only transient metabolic depletion, our analysis revealed that females maintained much-stricter control of their own immune response; this was achieved by female-specific transcriptional induction of a peptidoglycan amidase that degrades peptidoglycan fragments liberated from bacteria after they are killed, effectively enabling the female immune response to monitor its own effectiveness and to shut down when no longer needed. Elimination of this mechanism improved bacterial killing by the female immune response. Thus, indirect costs associated with infection (i.e., immune activity) rather than pathogen-derived effects drove these sex-specific immune outcomes. This is not the first demonstration of a difference in infection outcomes between the sexes originating from differential regulation of innate immune sensing; in mice, muting the inhibitory receptor CD200 resulted in greater immune activity and viral clearance, but this effect was more pronounced in female mice (48). However, this is a case in which differential immune regulation between the sexes results from differential degradation of microbial immune elicitors.

Stricter regulation of the IMD pathway by females suggests that immune activity may come at a greater burden to them. Uninfected wild-type females had a median survival 9.6% greater than females injected with PBS, heat-killed E. coli, and live E. coli (SI Appendix, Table S1). In contrast, only injection with live E. coli affected male survival (down 11.7% from uninfected). Because heat-killed E. coli are able to activate the immune response without causing mortality (shown here and in ref. 49), these findings indicate that immune activation comes at a greater cost to females. Together, these data support the idea that the IMD response is costly and that its activity poses a greater burden to females, leading to sex-specific differences in indirectrather than pathogen-derivedpathology. An alternative idea is that the energy demand of E. coli infection in PGRP-LB flies, as indicated through the decrease in both circulating and stored carbohydrate, was pathogen derived rather than immune. Bacteria have been shown to utilize host resources during infection (15, 50, 51) and while this would be surprising in this infection as bacterial numbers were declining (and were also lower than in wild-type infection, in which carbohydrate loss was absent), it remains a possibility. Indeed, the depletion of circulating sugars and glycogen in PGRP-LB flies supports a model of pathogen-derived glycogenolysis (51).

Elimination of PGRP-LB resulted in increased expression of diptericin (an indicator of IMD pathway activity) and thus, unsurprisingly, PGRP-LB flies had fewer bacteria than wild-type over the first 6 h postinfection (Fig. 5B and SI Appendix, Fig. S7A). The absence of triglyceride loss in these animals, associated with increased immune responses and reduced microbial loads, suggests that in this infection, triglyceride is lost because of direct pathogen effects. We have recently shown that when flies infected with the gram-negative pathogen Francisella novicida were treated with antibiotics to keep bacterial numbers low, they did not exhibit infection-driven metabolic shifts (including triglyceride loss). In contrast, when bacterial numbers increased (still in the presence of antibiotic treatment), metabolic shifts during infection were again observed, suggesting that these changes were associated with bacterial load rather than being a direct effect of the antibiotics on metabolism (33).

The immune response, as we normally envision it, includes responses to infection that protect the host by killing pathogens or restricting their growth (resistance). In contrast, tolerance is defined as the ability to maintain health during infection. Experimentally, a more-tolerant host is one that remains healthy longer at a given pathogen load (52, 53). Recent years have seen increasing interest in tolerance, driven in part by the idea of improving tolerance as a therapeutic approach to infection. However, despite the large body of theory surrounding tolerance, the ability to detect tolerant phenotypes (54), and the identification of tolerance-associated genes (31, 52, 55), we still know very little about the fundamental mechanisms of tolerance. It has previously been shown that PGRP-LB contributes to infection tolerance (40); we show that this activity is in fact sexually dimorphic. Importantly, through our finding that the masculinization of the female fat body led to a reduction in PGRP-LB expression (Fig. 5E), this work also demonstrates that the sexually dimorphic PGRP-LB activity is mediated by sex-determinant pathways. Furthermore, we show that phenomenological differences in tolerance between the sexes can be used to identify fundamental mechanisms of infection tolerance and that the sex-specific regulation of inhibitors of immune signaling can underlie strong, complex differences in immune dynamics between the sexes.

w1118 flies and w1118; imd10191 were used as wild-type and IMD pathway mutants, respectively. The imd10191 line carries a 26-nucleotide deletion that frameshifts the IMD protein at amino acid 179, which is the beginning of the death domain (56). PGRP-LB mutant lines used were obtained from the Bloomington Stock Center and have been previously described (57). Both imd10191 and PGRP-LB were placed on our w1118 genetic background using isogenic balancer chromosome lines. For tra knockdown experiments, we used w1118; c564-Gal4 (fat body driver) and w1118; UAS-tra2-RNAi from Bloomington Drosophila Stock Center and the Vienna Drosophila Resource Center, respectively. Flies were maintained on a sugar-yeast diet (10% wt/vol autolyzed brewers yeast, 8% fructose, 2% polenta, and 0.8% agar, supplemented with 0.075% wt/vol nipagin and 0.75% vol/vol propionic acid) at 25 C.

For all experiments, flies were collected within 24 h following eclosion and kept in same-sex vials for 5 to 7 d in groups of 20. Thus, all experiments were conducted on flies between 5 and 8 d old. Injections were carried out using a pulled-glass capillary needle and a Picospritzer injector system (Parker). Following injection, flies were kept at 29 C. Bacteria were grown from single colonies overnight at 37 C shaking. Each fly was injected with 50 nL of E. coli suspended in PBS (optical density at 600 nm [OD600] = 1.0 100,000 bacteria). Following resuspension in PBS, a subset of bacteria designated for the heat-killed treatment was incubated for 1 h at 65 C. Sterile PBS was used as a wounding control. A subset of imd flies were preinjected with 0.2-m latex beads, FluoSpheres, Carboxylate-Modified Microspheres (Invitrogen) to inhibit phagocytosis as previously described (30, 56). Briefly, beads were washed 3 in sterile PBS and resuspended in PBS at one-fourth of the original volume of the bead stock. Flies were injected with 50 nL bead-PBS solution or PBS alone, left for 16 h, and then injected with PBS or E. coli.

Survival experiments were performed at 29 C with 15 to 20 flies/vial. Survival was monitored daily, and flies were tipped into fresh vials every 4 d.

For each sample, one fly was homogenized in 100 L sterile ddH2O. Homogenates were serially diluted and plated onto Luria-Bertani (LB) agar plates where they incubated for 16 to 18 h. Following incubation, the number of individual bacterial colonies observed on each plate was quantified and back calculated to determine the number of colony-forming units (CFU) present in each fly. Individual fly quantifications are presented in SI Appendix, Fig. S8.

For each sample, three flies were homogenized in 100 L single-step RNA isolation reagent TRI Reagent (Sigma), followed by a chloroform extraction and precipitation in isopropanol. The resultant pellet was then washed with 70% ethanol. Pellets were resuspended and subject to DNase treatment. Revertaid M-MuLV reverse transcriptase and random hexamers (Thermo Fisher Scientific) were used to carry out complementary DNA (cDNA) synthesis. A volume of 5 L from each cDNA sample was put into a neat standards tube; this tube was later used to generate standards which were used to generate a standard curve for each gene. Each cDNA sample was diluted and this diluted sample used for analysis.

We used Sensimix with SYBR Green no-ROX (Bioline) or qPCRBIO SyGreen Mix Separate-ROX (PCR Biosystems) for qRT-PCR. Reactions were run on a Corbett Rotor-Gene 6000 with cycling conditions as follows: Hold 95 C for 10 min, then 45 cycles of 95 C for 15 s, 59 C for 30 s, and 72 C for 30 s, followed by a melting curve. Primers used are listed in Table 1. Gene expression was calculated based on the standard curve generated during each run, normalized to the value of our housekeeping gene, Rpl4. Samples from PBS and infected treatments were then divided by the mean value of their uninfected controls to generate expression values relative to uninfected flies.

Primer sequences used for qRT-PCR

All gene expression experiments were performed at least twice, with three or more biological replicates per experiment.

Triglycerides were measured using thin layer chromatography (TLC) assays as described elsewhere (58). Briefly, each sample consisted of 10 flies; flies were placed in microcentrifuge tubes and stored at 80 C until the time of analysis. To perform the TLC assay, samples were removed from the 80 C freezer and spun down (3 min at 13,000 rpm at 4 C) in 100 L 3:1 (vol/vol) mix of chloroform and methanol. Flies were then homogenized and subject to a further quick spin. Standards were generated using lard dissolved in the same chloroform: methanol solution. We loaded 2 L each standard and 20 L each sample onto a silica gel glass plate (Millipore). Plates were then placed into a chamber preloaded with solvent (a 4:1 [vol/vol] mix of hexane and ethyl ether) and left to run until the solvent reached a point 1 cm short of the edge of the plate. Plates were then removed from the chamber, allowed to dry, and stained with cerium ammonium molybdate (CAM) solution (58). Plates were baked at 80 C for 15 to 25 min and imaged using a scanner. Triglyceride was quantified in Image J using the Gel Analysis tool.

Each sample consisted of three flies that were homogenized in 75 L Tris-EDTA buffer (TE) + 0.1% Triton X-100 (Sigma Aldrich). Samples were incubated for 20 min at 75 C and stored at 80 C. Prior to the assay, samples were incubated for 5 min at 65 C. Following incubation, 10 L from each sample was loaded into 4 wells of a 96-well plate. Each well was designated to serve as a measurement for either: control (10 L sample + 190 L H20), glucose (10 L sample + 190 L glucose reagent [Sentinel Diagnostics]), trehalose (10 L sample + 190 L glucose reagent + trehalase [Sigma Aldrich]), or glycogen (10 L sample + 190 L glucose reagent + amyloglucosidase [Sigma Aldrich]). A standard curve was generated by serially diluting a glucose sample of known concentration and adding 190 L glucose reagent to 10 L each standard. Standards were always run at the same time and in the same plate as samples. Plates were incubated for 1.5 to 3 h at 37 C, following which the absorbance for each well at 492 nm was determined using a plate reader.

Respiration in flies was measured using a stop-flow gas-exchange system (Q-Box RP1LP Low Range Respirometer, Qubit Systems). Eight flies from each treatment were put into an airtight glass tube and supplied with our standard fly food via a modified pipette tip. Each tube was provided with CO2-free air, while the spent air was concurrently flushed through the system and analyzed for its CO2 and O2 content. In this way, evolved CO2 and consumed O2 were measured for each tube every 44 min (the time required to go through each of the seven vials in sequence). For most replicates of the respirometry assay, there were two uninfected, two PBS, and three infected vials.

Flies were collected within 7 h of eclosion to ensure virginity. To assess fitness, immediately following injection with either PBS or E. coli, flies were placed into vials with uninfected competitors of the same sex and potential mates of the opposite sex. Competitor flies expressed DsRed marker eyes; this marker allowed for easy identification of offspring resulting from focal fliesany DsRed-eyed offspring were the progeny of competitor flies. Flies were allowed to mate for 12 h, as this interval exceeds the time required for flies to significantly reduce the number ofand by some reports, clearE. coli, thus allowing us to observe fitness throughout the infection. In one block, E. coli reproductive assays were left for 24 h; we have included these data, as number of offspring produced did not differ from the shorter assay, possibly because females do not lay many eggs overnight. After the mating period, flies were discarded, and vials were left for 14 d to allow resultant offspring time to develop and eclose.

Data were analyzed in R Studio with R version 3.5.1 (59). Survival data were initially analyzed using Cox proportional hazards models; we then used Log-Rank tests for pairwise comparisons. We ran a generalized linear model (GLM) of reproductive success by sex and infection treatment; then, using only those matings resulting in offspring, we performed a GLM on number of offspring produced by sex and infection treatment. Detailed fitness and survival data have been deposited (60). For all other assays, we first tested for normality of data which dictated whether a factorial ANOVA model, Students t test, KruskalWallis ANOVA, or MannWhitney U test was used to calculate differences between treatments with sex and infection status as factors. Initial models included experimental replicate as a factor, which was removed once we failed to observe an effect. When appropriate, we performed post hoc Tukey or Dunn analyses to identify specific differences between treatments.

All data are provided in the paper and supplements; detailed fitness and survival data have been deposited at Research Data Repository (DOI: 10.14469/hpc/8546).

Members of the M.S.D. laboratory, the Imperial South Kensington fly laboratory, and D. Duneau provided useful feedback on the manuscript. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40 OD018537) were used in this study. Fly genetic and genomic information was provided by FlyBase (supported by NIH Grant U41 HG000739 and Medical Research Council (MRC) Grant MR/N030117/1). This work was supported by MRC Research Grant MR/R00997X/1 and Wellcome Trust Investigator Award 207467/Z/17/Z.

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Disparate regulation of IMD signaling drives sex differences in infection pathology in Drosophila melanogaster - pnas.org

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Ninety-nine Percent of all Clarkson University employees are fully vaccinated for COVID-19 – Clarkson University News

Wednesday, August 4th, 2021

Clarkson University announced this past Friday to its campus community that 99% of its more than 750 employees are fully vaccinated for COVID-19 with all employees at all campuses providing documentation or a request for a medical or religious exemption, two days ahead of an internal deadline set for August 1.

As nationally more corporate employers and government entities are requiring vaccination for employees, Clarkson is believed to be among the first private higher education institutions in the nation for its employees to reach this level of readiness to protect themselves as well as their community.

Learning that 99% of employees had received vaccinations was a testament of our employees commitment to the health of our community. I am proud to work at an institution that understands science, believes in safety and acts for the benefit of our community, said Lenn Johns, Founding Dean of the Lewis School of Health Sciences. Dr. Johns earned his PhD in cellular and molecular biology with a focus in immunology and regulation of the immune system.

"Clarkson's achievement of having more than 99% of our employee's vaccinated speaks to the dedication of the University to several of its core values: caring, teamwork, and service. Clarkson is an integral part of a rural community, and setting the example of getting vaccinated and protecting the community is of utmost importance with respect to keeping our community safe and healthy. We hope that we can lead by example in the fight against COVID," said Joan Caruso, MPAS, PA-C, Clarkson Physician Assistant Program Director and Chair, and Clinical Assistant Professor.

Known as a STEM career powerhouse, Clarkson faculty and staff as well as students have been following the science throughout the pandemic.Clarkson faculty have provided regular seminars to the larger University community and have been on the national stage with their expertise, fundamental research and applied innovation regarding the airborne transmission of the virus and other air contaminants.

This has created a community that understands the significance of reducing the risk of infection in order to provide the safest learning and living environment for all students in an in-person, largely residential environment.

Examples of press already covering faculty expertise are below.

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Ninety-nine Percent of all Clarkson University employees are fully vaccinated for COVID-19 - Clarkson University News

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Heres Who Is Hospitalized for Covid in New York City as Cases Rise – The New York Times

Wednesday, August 4th, 2021

Since early July, the average number of coronavirus cases in New York City has quadrupled, from about 250 to more than 1,000 per day, as the more contagious variant Delta has spread.

Hospitalizations are also rising, though not as quickly, thanks to vaccinations and improved treatments.

Still, hospitalizations are up 90 percent since July 4, and more than 300 people are now hospitalized in New York City with Covid-19. They are, for the most part, unvaccinated, or vaccinated but immunocompromised, doctors say.

A week and a half ago, we had 50 patients in our hospital systems, said Dr. Mangala Narasimhan, the senior vice president of critical care for Northwell Health, the states largest health system. Now we have double that.

To shine a light on who is getting hospitalized, city officials provided The New York Times with an age breakdown of people being admitted with Covid-19 between June 15 and July 12. Two of the main hospital systems operating in the New York City area, Mount Sinai and Northwell, also provided demographic and vaccination data for their patient population. Heres what the information shows.

Citywide, young adults, 25 to 34 years old, were the age group with the most people hospitalized with Covid-19 between June 15 and July 12, according to the citys Department of Health. This is in keeping with nationwide trends showing that the average age of Covid patients is skewing younger, largely because more older people are vaccinated.

Of the 627 people hospitalized during that stretch, 18 percent were 25 to 34 years old. The second most common age group for hospitalizations was people over 75. The city did not provide any information about vaccination status.

In the city, the full vaccination rate of people between 25 to 34 is 57 percent, and for people 75 to 84, it is 70 percent.

Hospitalizations among children for Covid-19 in the city remain rare, but they do happen. Over that month, nine children under 4 years old, and 10 children between ages 5 and 12, were hospitalized with Covid-19.

The two private hospital systems said that the average age of people they are admitting is declining, reflecting the citywide trend, though the average age in their systems remains above 50.

The average age among the 109 patients hospitalized as of July 27 in the Northwell system was 63, dropping to 57 among those who were unvaccinated. At Mount Sinai, the average age of hospitalized Covid patients this month was 55, down from 62 earlier in the pandemic.

The coronavirus vaccines are highly effective in protecting against serious disease, but they are not a guarantee. This is especially the case for a subset of elderly and immunosuppressed people whose immune system did not mount a strong response to the shots.

In the regular patient wards of Mount Sinai Hospital and Mount Sinai Queens, there were 14 unvaccinated patients and three partially vaccinated patients as of Wednesday, said David Reich, president of the hospital system. And, perhaps surprisingly, four of the five Covid patients in the intensive care unit were vaccinated.

Aug. 3, 2021, 9:15 p.m. ET

Of those, two are quite elderly, he said, and the other two were organ transplant recipients who had been taking medications to keep their immune system suppressed. The fifth is a person who is younger, morbidly obese and was not vaccinated.

It is a scary time for us, because even though we have highly effective vaccines, nothing is 100 percent, Dr. Reich said. And so it says to us that if you are a vulnerable person, even if you are vaccinated, you should probably take some precautions.

In the Northwell system, 10 to 15 percent of patients hospitalized with Covid-19 in recent weeks have been vaccinated. As at Mount Sinai, those who are vaccinated and severely ill are on chemotherapy, high-dose steroids, elderly or otherwise immunosuppressed.

We really havent seen healthy people who are vaccinated in the hospital with no other problems, said Dr. Narasimhan.

Understand the State of Vaccine Mandates in the U.S.

Even among the elderly, vaccines are still offering a great deal of protection. Nationwide, outbreaks and case rates in nursing homes remain at a fraction of their peaks. There have been several outbreaks in nursing homes locally recently, Dr. Narasimhan said. But for the most part, she said, those sick seemed to be able to deal with the infection in a different way than before being vaccinated and managed to be treated as outpatients.

We are not seeing a lot of severe breakthrough disease in vaccinated elderly yet, she said.

The people most likely to get severely sick now are the same as in previous waves, the hospital executives said. Obesity, diabetes and hypertension, among other factors, predispose people to severe illness.

The racial breakdown of admitted patients also seems similar to earlier waves, with a few exceptions. Northwell noticed a small uptick in the percentage of patients who were unvaccinated and white. Mount Sinai also noticed a small uptick in white patients, and fewer Asian American patients, but cautioned the sample size was too low to draw conclusions yet.

Hospital executives are also noticing how Delta is much more infectious than previous variants of the virus. Dr. Narasimhan said Long Island Jewish Hospital has had two recent situations where adult families grandparents, parents and grown children all developed severe Covid-19 after a relatively brief exposure to an infected relative, such as a 10-minute drive together, or a single meal.

The hospital has also definitely seen cases where vaccinated people have transmitted Covid-19 to unvaccinated people, she said. The Centers for Disease Control and Prevention says that vaccination reduces the risk of getting symptomatic Delta by sevenfold, and severe Covid-19 by twentyfold. Still, vaccinated people can carry substantial amounts of the virus, which is a key reason the C.D.C. now recommends that even vaccinated people in high and substantial transmission areas like New York City and Long Island wear masks indoors.

Amid all the scary developments, there is also hopeful news.

Northwell and other hospital systems are using monoclonal antibodies successfully to keep people with Covid out of the hospital. Under an emergency use authorization, the treatments can only be given to patients who are over 65 or at high risk of progressing to severe Covid.

Like other antivirals, monoclonal antibodies have to be given quickly, within a week of symptom onset. One problem is that some people are not getting tested or seeking treatment until they are short of breath with the onset of pneumonia, which tends to happen around Day 8. At that point its too late, said Dr. Reich.

The message, he said, particularly for those with risk factors, is Get tested, even if you are vaccinated.

Another positive sign is that hospitals are way below their peaks in terms of admitted patients with Covid. (At their height, in April 2020, New York City had almost 19,000 people admitted to hospitals with Covid.) As a result, hospitals are not overwhelmed and can deliver good care.

Despite the increased transmissibility of Delta, both Mount Sinai and Northwell reported that the percentage of patients progressing to intensive care is about the same as in previous waves, another promising development. Dr. Rahul Sharma, chief of emergency medicine at NewYork-Presbyterian/Weill Cornell, said that his doctors are noticing people are coming in earlier and less sick than in earlier waves, giving them a better chance of positive outcomes.

All of these are reasons the death rate in the city and state has remained low so far. About three people per day are dying of Covid-19 in New York City, a rate that has stayed stable for the past month even as cases rise.

Read more from the original source:
Heres Who Is Hospitalized for Covid in New York City as Cases Rise - The New York Times

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Mayor Carter and Mayor Frey Issue New Masking Guidance amid Delta Variant Spread and COVID-19 Case Increases in Twin Cities – StPaul.gov

Wednesday, August 4th, 2021

FOR IMMEDIATE RELEASEAugust 3, 2021

Contact:Peter Leggett651-307-8603peter.leggett@ci.stpaul.mn.us

In following latest CDC recommendations, Mayors recommend usage of masks in all indoor public spaces, and requiring masks for local government staff while indoors, as well as all visitors to City-owned buildings

SAINT PAUL, MN Today, Saint Paul Mayor Melvin Carter and Minneapolis Mayor Jacob Frey issued new masking guidance for indoor space in the Twin Cities along with requirements for the local governments staff and City-owned buildings. As data continues to emerge demonstrating the Delta variants heightened rate of transmission among both vaccinated and unvaccinated residents, the mayors are following recommendations from the Centers for Disease Control (CDC) and encouraging everyone to resume masking when indoors and requiring masks for those in City-owned buildings and City staff.

"This pandemic is far from over,said Mayor Melvin Carter.These measures will help protect us as we continue our work to get our entire community vaccinated."

Get vaccinated,said Minneapolis Mayor Jacob Frey.Getting the vaccine will help protect you and your neighbors from a deadly virus and it is the single most important action we can all take to curb the need for further restrictions.

Recent new guidance from the CDC recommends fully vaccinated people wear masks indoors in areas with substantial (50-100 cases per 100,000) or high (100+ cases per 100,000) transmission of COVID-19. On July 29, 2021, the CDC COVID-19 data track changed Ramsey Countys level of community transmission to substantial, triggering the CDC recommendation for fully vaccinated people to wear masks in public indoor settings.

Saint Paul-Ramsey County Public Health officials and city leaders will revisit this recommendation in the coming weeks as they continue to monitor transmission rates, hospitalizations, deaths, and increasing vaccination rates in the City and throughout the region.

Businesses are urged to adopt universal masking requirements for customers entering indoor areas of their businesses to provide better protection to their employees and customers. Also in accordance with CDC guidelines, restaurants and bar owners are encouraged to follow CDCs guiding principles for promoting behaviors that reduce virus spread, maintaining healthy environments and operations, and preparing for when an employee gets sick.

Both mayors are exploring options regarding a vaccine requirement.

ABOUT CDC RECOMMENDATIONTo maximize protection from the Delta variant and prevent possibly spreading it to others, wear a mask indoors in public if you are in an area of substantial or high transmission. Wearing a mask is most important if you have a weakened immune system or if, because of your age or an underlying medical condition, you are at increased risk for severe disease, or if someone in your household has a weakened immune system, is at increased risk for severe disease, or is unvaccinated. If this applies to you or your household, you might choose to wear a mask regardless of the level of transmission in your area. You should continue to wear a mask where required by laws, rules, regulations, or local guidance.

ABOUT CITY OF SAINT PAUL EXECUTIVE ORDER 2021-33Executive order 2021-33 requires all individuals regardless of vaccine status at City-Controlled Property to wear a face covering indoors at all times. Employees who are not in a congregate setting and are alone in their assigned workspace may refrain from wearing a face covering. City of Saint Paul employees and visitors are not required to wear a face covering while outdoors, unless at an activity specifically designated and posted by the City as requiring a face covering.

The order will apply to all individuals except young children at risk of suffocation and persons who cannot medically tolerate wearing a face covering. Acceptable face coverings include manufactured or homemade cloth face coverings, and are not required to be medical-grade masks. Face coverings must fully cover a persons nose and mouth.

All businesses are strongly encouraged to require that all individuals, regardless of vaccine status, wear a face covering indoors.

View Executive Order 2021-33here.

Read more here:
Mayor Carter and Mayor Frey Issue New Masking Guidance amid Delta Variant Spread and COVID-19 Case Increases in Twin Cities - StPaul.gov

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

Sunday, May 2nd, 2021

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sunday, May 2nd, 2021

'); if(!WVM.IS_STREAMING){ $videoEl.append('' + '' + ''); } setTimeout(function(){ $('.mute-overlay').on('touchstart click', function(e){ if(e.handled === false) return; e.stopPropagation(); e.preventDefault(); e.handled = true; player.muted(false); //console.log("volumee " + WVM.activePlayer.volume()); $(this).hide(); $(this).css('display', 'none'); var currentTime = player.currentTime(); if(currentTime 0){ if(deviceName == 'desktop'){ WVM.VIDEO_TOP = $('#media-container-' + videoId).offset().top; }else{ WVM.VIDEO_TOP = $('#media-container-' + videoId).offset().top - $('.next-dropdown-accordion').height(); } if(deviceName == 'desktop'){ WVM.VIDEO_HEIGHT = $('#html5-video-' + videoId).outerHeight(); }else{ WVM.VIDEO_HEIGHT = $('#html5-video-' + videoId).outerHeight(); } WVM.CONTAINER_HEIGHT = $('#media-container-' + videoId).height(); //console.log("container height: " + WVM.CONTAINER_HEIGHT); $(window).on( "resize", function() { if(deviceName == 'desktop'){ WVM.VIDEO_TOP = $('#media-container-' + videoId).offset().top; 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}, error : function(){ console.log("Error loading video"); } }); } }); } }; WVM.setupAccordionButton = function(fullVideoId){ var deviceName = 'desktop'; $('#next-dropdown-accordion-button-' + fullVideoId).on('click', function(){ if($(this).find('i').hasClass('fa-chevron-up')){ //hide $(this).find('i').removeClass('fa-chevron-up'); $(this).find('i').addClass('fa-chevron-down'); if(deviceName == "desktop" && !$('#media-container-' + fullVideoId).hasClass('floating-video')){ $('#media-container-' + fullVideoId + " " + '.page-carousel-wrapper').slideUp(); $('#media-container-' + fullVideoId + " " + '.mobile-list-wrapper').hide(); }else{ $('#media-container-' + fullVideoId + " " + '.mobile-list-wrapper').slideUp(); $('#media-container-' + fullVideoId + " " + '.page-carousel-wrapper').hide(); } var currVideoId = WVM['player_state' + fullVideoId]['VIDEO_ID']; var nextVideoId = WVM.getNextPlaylistIndex(currVideoId); //playerId, mediaId, fieldName var myTitle = WVM.getPlaylistData(fullVideoId, nextVideoId, 'noprefixtitle'); 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} } } $('#video-slider-nexttitle' + fullVideoId).css('display', 'none'); } }); var currVideoId = WVM['player_state' + fullVideoId]['VIDEO_ID']; //console.log("current Video " + currVideoId); var nextVideoId = WVM.getNextPlaylistIndex(currVideoId); var myTitle = WVM.getPlaylistData(fullVideoId, nextVideoId, 'noprefixtitle'); //console.log("setting title " + myTitle); $('#video-slider-nexttitle' + fullVideoId).css('display', 'inline'); $('#video-slider-nexttitle' + fullVideoId).html(myTitle); }; WVM.sendbeacon = function(action, nonInteraction, value, eventLabel) { var eventCategory = 'Video'; if (window.ga) { //console.log("sending action: " + action + " val: " + value + " label " + eventLabel); ga('send', 'event', { 'eventCategory': eventCategory, 'eventAction': action, 'eventLabel': eventLabel, 'eventValue': value, 'nonInteraction': nonInteraction }); } }; WVM.getNextPlaylistIndex = function(mediaId, returnArrayIndex){ var currId = null; if(mediaId == null){ return null; } for(var x =0; x 20){ if(fullDuration > 1 && ((fullDuration - fullCurrent) > 1) && !$('.vjs-loading-spinner').hasClass('badspinner')){ console.log("hiding spinner"); $('.vjs-loading-spinner').addClass('badspinner'); } } var duration_time = Math.floor(this.duration()); //this is a hack because the end video event is not firing... var current_time = Math.floor(this.currentTime()); if ( current_time > 0 && ( fullCurrent >= (fullDuration - 10) )){ var currId = playerState.VIDEO_ID; var newMediaId = WVM.getNextPlaylistIndex(currId); //if(playerSettings.autoplay_next && newMediaId){ if(newMediaId){ if('desktop' == "iphone" && playerState.AD_ERROR){ console.log("skipped timeupdate end"); }else{ WVM.load_video(newMediaId, true, playerState.ORIGINAL_ID); } } } if(!playerState.START_SENT){ WVM.sendbeacon('start', true, playerState.VIDEO_ID, playerState.VIDEO_TITLE); playerState.START_SENT = true; } var currentTime, duration, percent, percentPlayed, _i; currentTime = Math.round(this.currentTime()); duration = Math.round(this.duration()); 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if(theVolume > 0.0 || cssVolume > 0){ $('#media-container-' + playerState.ORIGINAL_ID + ' .mute-overlay').css('display', 'none'); }else{ $('#media-container-' + playerState.ORIGINAL_ID + ' .mute-overlay').css('display', 'block'); } }); WVM.reinitRawEvents(playerState.ORIGINAL_ID); setInterval(function(){ WVM.reinitRawEvents(playerState.ORIGINAL_ID); }, 2000); } if(!WVM.rawCompleteEvent){ WVM.rawCompleteEvent = function(e){ var playerState = WVM['player_state155200']; console.log("firing raw event due to all other events failing"); var currId = playerState.VIDEO_ID; var newMediaId = WVM.getNextPlaylistIndex(currId); //if(playerSettings.autoplay_next && newMediaId){ if(newMediaId){ WVM.load_video(newMediaId, true, playerState.ORIGINAL_ID); } }; } if(!WVM.rawTimeupdateEvent){ WVM.rawTimeupdateEvent = function(e){ var playerState = WVM['player_state155200']; var rawVideoElem = document.getElementById('html5-video-' + playerState['ORIGINAL_ID'] + '_html5_api'); var fullCurrent = rawVideoElem.currentTime * 1000; var fullDuration = rawVideoElem.duration * 1000; var current_time = Math.floor(rawVideoElem.currentTime); console.log("raw timeupdate: " + fullCurrent + " out of " + fullDuration); if ( current_time > 0 && ( fullCurrent >= (fullDuration - 50) )){ var currId = playerState.VIDEO_ID; var newMediaId = WVM.getNextPlaylistIndex(currId); if(newMediaId){ console.log("loading new video from rawtimeupdate"); WVM.load_video(newMediaId, true, playerState.ORIGINAL_ID); } } if(!$('.vjs-loading-spinner').hasClass('badspinner')){ $('.vjs-loading-spinner').addClass('badspinner') } }; } WVM.reinitRawEvents = function(playerId){ var playerState = WVM['player_state' + playerId]; var rawVideoElem = document.getElementById('html5-video-' + WVM['player_state' + playerId]['ORIGINAL_ID'] + '_html5_api'); //COMPLETE EENT if( WVM['player_state' + playerId].COMPLETE_EVENT){ rawVideoElem.removeEventListener('ended', WVM.rawCompleteEvent, false); } rawVideoElem.addEventListener('ended', WVM.rawCompleteEvent, false); //TIME UPDATE EVENT if( WVM['player_state' + playerId].TIMEUPDATE_EVENT){ rawVideoElem.removeEventListener('ended', WVM.rawTimeupdateEvent, false); } rawVideoElem.addEventListener('ended', WVM.rawTimeupdateEvent, false); WVM['player_state' + playerId].COMPLETE_EVENT = true; WVM['player_state' + playerId].TIMEUPDATE_EVENT = true; };

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sunday, May 2nd, 2021

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

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

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

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

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

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

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

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

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

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

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

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