FoundMyFitness - #055 COVID-19 Q&A #2 - Antibody-Dependent Enhancement, Cross-Immunity, Immunity Duration & More

Episode Date: June 10, 2020

This is a continuation of the last episode where Dr. Patrick took questions from newsletter subscribers around the ongoing pandemic and tried to add value by talking about some of the recent research, among other things. In this episode, you'll discover: (00:00) Introduction (04:06) Data surrounding SARS-CoV-2 duration (06:30) SARS-CoV-2 and long-lasting immunity (11:27) Genetic causes of immune variation (14:27) Previous viral exposure and cross-immunity to SARS-CoV-2 (18:57) Antibody-dependent enhancement and SARS-CoV-2 relevance (21:50) Sleep deprivation impairs immunity & vaccine efficacy (23:42) Microbiome composition and immune function (28:22) The differential effects of exercise intensity and duration on immune regulation (34:10) Micronutrient inadequacies promote immune dysregulation (46:32) Effects of sex and age in immune regulation (48:59) Controversy surrounding hypertension drugs such as ACE inhibitors and COVID-19 (52:28) ARDS and long-term lung damage If you're interested in learning more, you can read the full show notes here. Join over 300,000 people and get the latest distilled information straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Hello, friends. I'm excited to share the second round of our COVID-19 Q&A with you. This is a continuation of the last episode where I took questions from newsletter subscribers around the ongoing pandemic and try to add value by talking about some of the recent research. Let's talk COVID-19. Some sources suggest that the case fatality rate worldwide is on the decline, and that's great news and probably in a large part explains why we're not hearing as much about COVID-19 right now. However, we are still in the middle of a pandemic. So I hope that this episode offers some value in light of that. It's important to note up front, and I say this emphatically.

The content in this episode is not meant to diagnose any disease and is not intended for medical treatment. I am not a medical doctor, and the information I share does not constitute medical advice. My background is in science and not medicine. With that said, some of the topics that came up as a result of the questions specifically, submitted from the newsletter subscribers include some of the discussions surrounding what we know about the duration of the SARS-CoV-2 virus, whether or not exposure leads to ultimate immunity, et cetera. Some of the main factors known to play a role in immune variation, including what role genetics

may play in immune function, how previous viral exposure regulates immunity, what cross-immunity is and how it may be relevant for SARS-CoV-2. Antibody dependent enhancement and SARS-CoV-2 relevance. How sleep is a key regulator of immune function. Microbiome composition and immune function. The differential effects of exercise intensity and duration on immune regulation. How specific micronutrient inadequacies may promote immune dysregulation. The effect of sex hormones on immune function.

How biological age may play a role in immune regulation. We also discuss some of the data surrounding hypertension, drug such as ACE inhibitors and ARBS and COVID-19. And finally, we discuss ARDS and the long-term lung damage. Okay, one more mention. This is it. Really. We've recently released an updated genetic report version 8.

If you have raw genetic data from a popular provider like 23 and Me or Ancestry DNA, you can run from my website a private, standalone, and downloadable, interactive, tagged, categorized, fully searchable report. The most recent update transformed this report in terms of utility from a basic PDF to something much more robust and you get to download and keep it. This potent version 8 update also adds a wide variety of entries that will be discussed in this very episode. Some of these genetic polymorphisms have been identified by the scientific community

to potentially impact Sarge Cove 2, as well as others involved in the immune response. Run this brand new report which mines useful little insights from your existing. genetic data files from found my fitness.com forward slash genetics. Or if you want to just get a PDF just on the entries related to this episode, you can get those for free by selecting the viral option under basic reports, also at found my fitness.com forward slash genetics. Let's start with the first question. After recovery, how long does the virus stay in your body? Can it flare up in the future? Can you get reinfected? Does exposure lead to immunity? So let's address the first part of this question. How long does the virus stay in the body? Studies have suggested once infected, it takes 4 to 7 days

for symptoms to develop. Four to five days after the onset of symptoms is when symptoms peak and people are most infectious. By 10 days after onset of symptoms, there is still measurable viral RNA in the sputum, but the risk of spreading the virus is minimal. A study from JAMA found that even though patients tested positive for coronavirus up to two weeks after symptoms have stopped, they no longer transmitted the virus to close contacts. These patients were discharged from the hospital after 72 hours of no symptoms, and no family members contracted the disease once they were sent home. The Lancet recently published similar data. From the time of symptom onset, most people test negative by day 20. The longest period by which a person tested positive from onset of symptoms

was 37 days. Given that the symptoms last up to two weeks, this is consistent with the JAMA study. Okay, the second part of this question is whether a person can have a flare-up. This has been circulating in the media since COVID-19 patients in Korea were reported to test positive

shortly after recovering from the disease. The three causes could be reinfection, a relapse, or inconsistent RTPR tests. An overly sensitive RTPCR test might be detecting non-infective RNA-Firm. fragments rather than infectious viral particles. A study from the Korean CDC traced 790 close contacts of 285 people who retested positive and found that none of the close contacts became infected. Researchers tested respiratory samples from 108 of the repositive cases and could not isolate

the intact virus. Of the 23 repositive cases from whom the first and second serum samples were obtain, 96% were positive for neutralizing antibodies. It seems unlikely for the SARS-CoV-2 virus to cause a flare-up in the future because SARS-cove-2 is a single-stranded RNA virus and does not have the enzyme reverse transcriptase. Without reverse transcriptase, the virus is not able to insert into DNA and cause flare-ups in the future, like other viruses such as HIV, varicelizoster virus or herpes virus, which all have a reverse transcriptase component. The last part of this question is, can a person become reinfected? This has to do with the adaptive immune system. Generally, after recovery from a virus, the body has developed specific antibodies such as memory B cells to prevent

future reinfections. How long immunity lasts depends on the virus. With some viruses such as measles morbillivirus, which causes measles, infection confers almost universal life-lifference. Infection confers almost universal lifelong lasting protection. On the opposite end of the spectrum, individuals infected with HIV often have antibodies that do nothing to fight HIV. Some viruses like HIV use multiple strategies to evade antibodies. So what about other coronaviruses? Antibody tithers in individuals that survived Sargecove one or Maerskove infections often waned after two to three years or were weak initially. However, one study showed that convalescent syria from SARS patients taken three and a half years after disease onset did neutralize the SARS-CoV-1 virus and even somewhat cross-neutralized

SARS-Cove 2 entry into the cell via the ACE-2 receptor. That suggests that SARS-Cove 1 antibodies are still able to neutralize the SARS-Cove 1 virus three and a half years after the initial antibody response. This study also provided some preliminary evidence that antibodies made in response to other coronaviruses may provide some cross-immunity against SARS-cove-2, although another study found that this was not the case, but we will come back to that later. In SARS-Cove 1 survivors, the CD8 T-memory cells persisted for 6 to 11 years, suggesting there may be long-term immunity. Additionally, coronaviruses responsible for the common cold induce antibody responses that neutralize the coronavirus that causes the common cold, but they don't appear to last and wane over

the course of one to two years. That means people can be reinfected with the exact same coronavirus one to two years later. It is still unclear how long antibodies generated from the SARS-CoV-2 infection and whether or not they confer protection. The immune system is not perfect, and over many years, the memory B cells may not recognize a virus that they were programmed to recognize. So there's no guarantee that you can't get reinfected at some point. Also, viruses often mutate or they find other ways to obey the immune system. There is a strain of the SARS-CoV-2 virus that has a mutation in a region of the virus that antibodies bind to.

Non-human primates infected with SARS-CoV-2 that recover and have antibodies do not become reinfected when re-exposed to the virus 28 days later. We know that people infected with SARS-Cove 2 do develop antibodies against the virus. A study found that out of 285 patients in China, with COVID-19, 100% of them developed antibodies against the SARS-CoV-2 virus within 19 days of viral exposure. The ability of those antibodies to neutralize the virus was not determined. But as I just mentioned, non-human primates that developed antibodies after recovering were not reinfected after being exposed to the virus a second time. And a study of 10 patients in China found a single dose of

convalescent plasma from patients that have recovered from COVID-19 and contained antibodies against Sargecove 2 resulted in a clearing of the virus in the patient's blood within seven days, clinical symptoms improved significantly within three days, and lung lesions improved within seven days. Antiquotes from other hospitals in the U.S. report the same. Studies of the common cold coronaviruses, Sarge Cove 1 and Maerscove indicate that virus-specific antibody responses wane over time and, in the case of common cold coronaviruses, antibody responses may only result in partial protection from reinfection.

These data suggests that immunity to SARS-CoV-2 may diminish following a primary infection, and further studies will be required to determine the degree of long-term protection. There are a few large serological surveys being led by Dr. Michael Bush, who is an MD PhD at the School of Medicine at UCSF, to look at antibody responses that are waning and to assess herd immunity. The handful of rare cases where people have tested positive after recovering from the disease could also be due to testing errors, as mentioned previously. Let's move on to the next question. Reports indicate the range of this virus in terms of symptoms is drastically wide,

ranging from fully asymptomatic to fatal. And despite earlier reports, there are significant deaths even among those under 50. What accounts for such variation person to person, especially among otherwise healthy people? Are there other viruses like this? Is it different viral strains or genetics, immune system types? There are likely many, many, many different reasons for the varied ways people respond to this virus. But right now, everything still remains speculation.

In general, differences in immune function between otherwise healthy individuals may be attributed to many factors, which we will discuss, including genetics, previous exposure to pathogens, sleep, microbiome composition, exercise, nutrition, gender, and biological age. A large part of the variation in immune function between individuals, particularly with respect to adaptive immunity, has been determined to be from non-heritable factors, which we are about to dive into, but genetics does account for some of this variation. The severity of a viral infection depends on the pathogenicity of the virus as well as the health status and genetic makeup of the host. Polymorphic regions referred to as single nucleotide polymorphisms, or SNPs, for short,

in various genes may affect the disease outcome of an infected individual. There are several large collaborative efforts underway to share and analyze genetic data to try and understand the links between human genetic variation and COVID-19 disease and severity. The largest one is called the COVID-19 host genetic initiative. Several SNPs have previously been identified to affect immune responses to the SARS-CoV-1 virus, and several studies have already identified several possible SNPs that may potentially impact susceptibility to COVID-19, although these remain to be tested in large genomic studies and clinical trials. There are some SNPs that affect general viral entry into the host cell, for example,

ACE-2, the host cell receptor for SARS-CoV-2, TMPR-S-S-2, a protease that cleaves the spice, protein allowing Sarge Cove 2 to enter the cell. IFITM3, a protein that interrupts the fusion between a virus and the cell membrane associated with severity of influenza. There are also a variety of SNPs that generally affect viral replication. There are also SNPs that affect the host immune response, ranging from cytokine production to viral induced inflammation. And there are snips that affect acute respiratory distress syndrome. There are also several snips that affect vitamin D levels. Genetically low plasma vitamin D levels are associated with a higher mortality from respiratory infections. And three different snips in the vitamin D receptor are all associated

with a higher risk of respiratory tract infections in both adults and children. Vitamin D is a very important regulator of immune function and plays a particularly important role in respiratory track infections. If you have used some consumer genetic testing, services like 23 and me and ancestry DNA, and you want to learn more about these SNPs, we put together a free viral report that you can find at foundmyfitness.com forward slash genetics. So let's dive into the non-heritable trades that account for a large percentage of immune variation. One big one is exposure to previous viruses. Broad serological profiling has revealed that at any given time, an individual carries

antibodies to about 10 different viral species. cytomegalovirus, or CMV for short, is a lifelong virus that has profound effects on the immune system, influencing everything from cytokine production to immune cell populations. One study found that the presence of CMV could enhance the immune response to the influenza vaccine in young people, and mice given CMV had protection against influenza virus compared to mice without CMV. So let's talk a little bit about exposure to previous pathogens and cross-immunity. virus neutralizing antibodies bind to a virus and prevent it from infecting a cell, usually by preventing it from binding to a receptor. SARS-CoV-2 belongs to the beta-coronavirus genus of coronavuses,

which includes the SARS-CoV-1, Maerscove, and two other human coronavuses, H-C-43, and H-C-U-1, which are responsible for some of the common cold. The beta-coronov-O-C-Rodivuses can, immune responses against one another, generating neutralizing and cross-reactive antibodies against each other. Previous studies have found that SARS-CoV-1 can generate neutralizing antibodies against H-C-403, which could offer cross-immunity and H-COV-O-C-43 can generate cross-reactive antibodies against SARS-Cove 1. Additionally, antibodies from Sera from people with

H-C-COV-O-C-43 coronavirus responsible for the common cold, were found to cross-react with Sarge-Cove 2 antibodies. It was also found that people infected with Sargecove 2 also increased their pre-existing antibodies against the classic cold coronavirus. Antibodies produced in response to infection from Sarge-Cove 1 cross-react with SARS-Cove 2 because the spike proteins for both viruses are similar enough to each other. While SARS-Cove-1 antibodies did not bind as tightly to SARS-CoV-2, another study showed that convalescent syrup from SARS-patients, that was three-and-a-half years post-infection,

did cross-neutralize SARS-Cove-2 entry into the cell via the 8-2 receptor. That suggests that SARS-Cove-1 antibodies may provide cross-immunity against SARS-Cove 2. However, a more recent study found that syrup from patients that had recovered from SARS-Cove 1 that was collected only 22 days after infection did not neutralize the SARS-CoV-2 virus. It's unclear why there are conflicting results, but there were some methodological differences in these studies. First and foremost, a major difference between the two studies is when the cirr was collected. In this study where there was indication of cross-immunity, samples were collected 3.5 years after infection. In the study where there was no cross-immunity, samples were

collected within 22 days post-symptom onset, which is fairly early in the maturation of the humoral immune response when antibody titers are still increasing. It is possible that some cross-immunity may have been detected if the samples were collected at a later time point. Another difference between the two studies is that they use different strains of the SARS-Cove 2 virus. One was the Hong Kong strain versus the Germany strain. Another study published in the Journal of Cell detected SARS-CoV-2 reactive CD4 positive T-cells in about 40 to 60% of unexposed individuals, suggesting cross-reactive T-cell recognition between circulating common cold coronaviruses and SARS-COF-2. These helper T-cells promote B-cells to produce antibodies

and the natural killer T-cells to target and destroy cells that are actively infected. 100% of recovered COVID-19 patients that were tested had SARS-CoV-2 specific helper T-cells, and 70% had natural killer T-cells. 68 blood samples from uninfected individuals found that 35% of these samples also had helper T-cells that recognized SARS-CoV-2 virus. The results suggest one reason that a large chunk of the population may be able to deal with a virus is that some people may have small residual immunity from exposure to common cold coronaviruses. So it is possible the immune memory to previous coronavirus infections may help ameliorate

symptoms of SARS-CoV-2 infection, but it is also possible that antibodies bind to the virus and do not neutralize it and perhaps even increase infection risk via antibody-dependent enhancement, which we are about to discuss. In either case, more data is needed. This also suggests that the antibodies from these common cold coronaviruses may complicate accuracy of SARS-cove-2 serological diagnostics, as people reinfected with common cold coronaviruses could score as false positive with some SARS-cove-2 serological assays. So let's talk a little bit about antibody-dependent enhancement. In antibody-dependent enhancement of infection, low quality, low quantity, non-neutralizing antibodies bind to virus particles through the fab domains.

FC receptors expressed on monocytes or macrophages bind to the FC domains of antibodies and facilitate viral entry and infection. The binding of these non-neutralizing antibodies can also form a complex with a virus that does not allow viral entry, but does activate signaling pathways that cause activation of immune cells and can result in severe immune-induced pathology. This is a real concern since antibody-dependent enhancement has been shown to occur with other coronaviruses such as SARS-cove-1 and Maerskove. Importantly, in all of the descriptions of antibody-dependent enhancement as it relates to coronavirus, the FCR was necessary to trigger the antibody-mediated pathology.

This has been shown to happen with monoclonal antibodies against the receptor binding domain in the spike protein of the Mares coronavirus. The monoclonal antibody mimicked binding to the receptor that caused a three-dimensional conformational change in the spike protein that allowed entry into the cell. Multiple factors determine whether an antibody neutralizes the virus and protects the host or causes antibody dependent enhancement and acute inflammation. These include specificity, concentration, affinity, and isototype of the antibody. Antibody dependent enhancements. also happens in SARS-Cove 1, but it did not result in more viral entry. Rather, it caused activation of immune cells and immune-induced pathology. This was shown to occur in non-human

primates given a vaccine against the SARS-Cove 1 spike IGG. Although in other two studies where non-human primates were given either a high-dose or low-dose vaccine against SARS-Cove 1, they did have protection against the virus and did not develop antibody-dependent enhancement. So it's not always the case. Let's move on and talk about another important factor that regulates immune function, sleep. This is an important issue because we live in a world of increasing demands on our time and decreasing hours of sleep. The relationship between sleep and immunity is important because in recent decades, there has been a documented decrease in the mean duration of sleep and an increase in shift work. While sleep requirements change depending on stages of development and can vary from

person to person, adults generally require seven to nine hours of uninterrupted sleep per night. To learn more about the importance of sleep on health, including immune function, check out our interview with Dr. Matthew Walker, who is the director of the Sleep Institute at UC Berkeley. Partial sleep deprivation can affect immunity. For example, humans immunized against infection with the influenza A virus during a period of partial sleep deprivation had virus-specific antibody titers less than half of those of non-sleep-deprived individuals at 10 days after immunization. Chronic sleep deprivation can also affect immune cell numbers.

For example, insomnia has been shown to be associated with significant decreases in the numbers of CD3-positive, CD-4-positive, and CD-8-positive T-cells, and with reduced natural killer cell responses. Insomnia and otherwise healthy individuals is related to low levels of interferon gamma and low interferon gamma to IL4 ratio, which could lead to a shift in the THH helper cells balance towards a TH2 dominance. THHelper cells as a part of adaptive immunity drive and control immune responses. The imbalance with TH2 dominant could lead to secondary infections, viral reactivations, and the inability to clear the initial infection, which has been improved in autoimmune diseases. Suffice to say, sleep is very important for immune function.

The microbiome is also important for immunity. Not all pathogens are bad, some are good. Emerging data over the last several years has unveiled important roles that commensal bacteria, which are often referred to as good bacteria, play in human health. The gut microbiome regulates immune cell populations. When fermentable fiber, which is the fiber that passes undigested into the colon is consumed, the bacteria break down some of the fiber for their own use. The byproducts of this bacterial action are several short chain fatty acids, including buterate, lactate, acetate, propionate, as well as other compounds. Short chain fatty acids are important for maintaining gut barrier function, but they also

play a special role in regulating cytokine production and immune cell populations. The gut microbiome directly influences immune cells that reside in the gut and indirectly influences immune cells outside of the gut via short chain fatty acids, including the production of T regulatory cells, which are immune cells that keep autoimmunity at bay. Many studies have found that short chain fatty acids derive from the gut microbiome promote the expansion of T regulatory cells. Reduced T regulatory cell numbers have been found in severe COVID-19 patients, and T regulatory cells have been shown to help resolve acute respiratory distress syndrome. So, reduced T regulatory cell numbers might lead to worse lung pathology.

Gut bacteria also used flavonoids found in fruits, teas, etc., to control the immune response and protect against severe damage from the influenza virus. The bacteria metabolized flavonoids and produced a compound called desamino-tyrosine, or dat, for short, which helped produce interferon, a signaling molecule that activates the immune system. This helped protect the lungs against damage from the flu virus. The DAT did not prevent the flu, but it did significantly reduce the severity of it. Some of the main dietary sources of flavonoids include tea, citrus fruit, berries, apples, and legumes.

Mice that were fed fermentable fiber, specifically inulin, had reduced mortality, better lung function and less tissue destruction after exposure to influenza virus compared to mice fed non-fermentable fiber, which was cellulose. Short-chain fatty acids derived from the fermentable fiber prevent, prevent. prevented neutrophils from infiltrating lung tissue, and this prevented lung tissue damage. The short chain fatty acids also enhance CD8 T-cell effector function and viral clearance. The microbiome also plays an important role during early life. Several studies have shown that early exposure to microorganisms in the dirt, particularly before

the first year of life, has been shown to significantly lower the risk of allergies, wheezing, and asthma in children. Early exposure to bacteria and certain allergens such as pet dander may have a protective effect by shaping the child's immune responses in such a way that prevent allergies and asthma. This becomes very important in infants that have genetic predisposition to allergies, eczema or asthma, particularly if a parent or sibling has one or more of those diseases. One study specifically found that wheezing was three times as common among children who grew up without exposure to such allergens compared to children who were exposed before their first year

of life. Interestingly, exposure to allergens after the first year of life, did not decrease the child's risk of developing allergies or asthma. Even exposure to certain species of bacteria in early life can have differential effects on the immune system, particularly with respect to autoimmunity. An imbalance between the so-called healthy or good bacteria and the pathogenic or bad bacteria referred to as dysbiosis also plays a role in shaping the immune system.

A healthy or dysbiotic microbiota can influence the host innate immune system via two types of signals, microbial cell components and metabolites. In a disbiotic state, alterations in the signature of microbial molecules sensed by the host can lean to different activation state of the immune system. For example, animal studies have shown that certain species of bacteria in the gut promote antibody responses to the influenza vaccine, TIV. They do this through generating a toll-like receptor 5 signal. In humans, it was shown that the same toll-like receptor 5 signal was correlated with a higher antibody tighter four weeks after the influenza vaccine. In a way, the gut microbiome acts like a

natural adjuvant, at least in animal studies. Ablating the gut microbiome in animals has been shown to affect the gut epigenome and transcriptional genome of lymphoid cells and the transcriptional genome of myloid cells. This occurs through triptophan metabolites and short chain fatty acids generated via the microbiome. Let's move on and discuss exercise. Exercise also affects immune function. Moderate exercise of one hour per day for five days a week has been shown to improve the immune system, but intense exercise for two hours or more has been shown to increase the risk of illness. This can be described as a J-curve. Another example of this J-curve response is a study including elite cyclists, recreational cyclists, and sedentary controls. Recreational cyclists had

the fewest number of sick days. Sedentary controls had twice as many sick days as recreational but elite cyclists had four times as many sick days as recreational cyclists. A 2019 review outlined nine studies where endurance exercise was shown to decrease the number of respiratory illnesses. The workouts in these studies ranged from 30 to 60 minutes and were moderate in intensity such as jogging. Antibody response to vaccination has been used as a proxy for immune response to exercise. A comprehensive review investigated the relationship between exercise and the immune response to a vaccine and found that in eight studies, frequent moderate to vigorous exercise increases the body's immune response to a vaccine. However, strenuous prolonged exercise did not

show as strong of an immune response. For example, prolonged intense exercise is unable to boost antibody responses to vaccines like moderate exercise was able to. One study vaccinated 22 male triathletes 30 minutes after completing a triathlon. There was no difference in antibody levels in the male triathletes compared to controls. There are several studies that demonstrate that extreme endurance exercise does not benefit the immune system and can increase the chances of getting respiratory illness. For example, the J-Curft study we mentioned earlier

found that elite cyclists had four times as many sick days as the recreational cyclists and twice as many as the sedentary group. Other studies have found an increased rate of respiratory illnesses after intense endurance exercises that last at least 90 minutes in life. length. Shorter duration running events such as five, 10 kilometers, and half marathons did not appear to elicit in increased incidence of self-reported upper respiratory track infections. Elite endurance athletes are exposed to many factors that could contribute to increase viral susceptibility. For example, they often attend events with large attendance, frequent traveling,

psychological stress, potential nutritional deficiencies, lack of sleep, and more. However, when compared to other athletes that attend the same events and have similar risk factors, the endurance athletes still have a significant increased risk of illness compared to, for example, power or speed athletes. There are a couple of proposed mechanisms that might explain why extreme exercise may depress immune function. But before talking about the proposed mechanisms, I think that it goes without saying that extreme exercise, like that at the elite level, is very energetically demanding. Immune cell activation, such as the case when fighting off a pathogen, is also very energetically demanding.

It seems very logical that there may be a triaging of the available energy to perform the exercise, since that it's being forced, thus leaving the immune system temporarily unable to function optimally without the necessary precursors and energy it requires. All right, with that said, let's discuss the proposed mechanism one. The open window theory is characterized by short-term. suppression of the immune system following an exercise. During exercise, stress hormones like cortisol increase in order to maintain adequate blood glucose. These stress hormones could transiently suppress immune function. Shorter exercises may not allow enough time for the pathogen to replicate, but a two-hour

plus exercise may allow enough time for it to replicate to a critical threshold that the innate immune system cannot resolve. Some argue that the decrease in immune cells after exercise supports this theory, but as we will later discuss, the decrease in immune cells may actually be due to a beneficial relocalization of immune cells from the blood to tissues. So let's talk about mechanism number two. The immune system cannot handle the pathogen burden associated with a two plus hour. While there may be a boost to the immune system in an intense two hour plus exercise, as there is in a moderate 45-minute exercise, the burden on the immune system hits a tipping point that leaves it depleted. In support of this theory is the observation that vitamin C demand is increased in long

endurance exercises. For example, six trials involving more than 600 marathon runners, skiers, and soldiers reported 50% fewer colds when supplementing with vitamin C. In addition, a randomized controlled study in 20 athletes in their early 20s who participated in dual-a-thon-like competitions found that antioxidant supplementation increased the antioxidant defenses of neutrophils. There has been some debate about whether very strenuous exercise suppresses immune function as a consequence of decreased immune cell numbers. White blood cell numbers have been shown to increase during acute bouts of exercise, followed by rapid reduction in immune cell numbers 30 to 60 minutes post-exercise. The drop in immune cell number can be 30 to 50% less than

pre-exercise levels and can last up to six hours. This increase and sequential decrease sparked the theory of the J-shaped curve. Although many studies have validated the J-shaped curve, the mechanism is no longer believed to be due to the rise and fall in immune cells. This is because the number of immune cells in the blood is not a good indicator of immune response. The increase of immune cells is due to the immune cells being pulled off of the edges of blood vessels by the increased blood flow and pressure. Afterwards, the decreases due to redistribution of immune cells to various tissues and out of the bloodstream. This has been shown in mice where fluorescent cell tracking

showed immune T-cell numbers rise during bouts of exercise, but then were redistributed primarily to the lung and other areas like the small intestine. If anything, the immune surveillance is actually heightened during the period where a few immune cells are measured in the blood. As a result, the mechanism behind the J-shaped curve of respiratory infection and exercise duration is not due to the number of immune cells.

in the blood. Let's move on and discuss nutrition, which also plays an important role in immune function. Most people in the United States are getting enough of their macronutrients, like protein, carbohydrates, and fats. But what people are not getting enough of are micronutrients. Micronutrients are about 30 essential vitamins, minerals, trace elements, essential fatty acids, and amino acids that must be obtained from our diets since we cannot make them. Many people in the U.S. are not obtaining adequate amounts of these micronutrients from their diets. For example, in the United States, 60% of the population has inadequate intake of vitamin E, 45% has inadequate intake of magnesium, 34% has inadequate intake of vitamin A,

25% has inadequate intake of vitamin C, 8% has inadequate zinc intake, omega-3 fatty acid intake is very, very low, and 70% of the U.S. population has insufficient vitamin D levels. Several vitamins including vitamins A, B6, B-12, C, D, D, and folate, and minerals and trace elements including zinc, iron, selenium, magnesium, and copper, play important and complementary roles in supporting both the innate and adaptive immune systems. Deficiolium, or insufficiencies in micronutrients negatively affect immune function and can decrease resistance to infections. Micronutrients support the integrity of physical barriers that inhibit infections, such as the skin and mucosal layers of the gut and respiratory tract. Micronutrients are also involved in producing antimicrobial proteins, in differentiation and motility, in phagocytic and killing activities of neutrophils and macrophages, and promotion of and recovery from inflammation.

Micronutrients, particularly vitamin C and D, support adaptive immunity via lymphocyte differentiation, proliferation, and homing, cytokine production, antibody production, and the generation of memory cells. Deficiencies or suboptimal status of these nutrients can impair immune functions by decreasing lymphocytes, impairing phygotosis, altering cytokine production, or reducing antibody response. It seems possible that suboptimal intakes of a range of micronutrients, could contribute to variation in immune outcomes that is seen in the general population. Let's talk about a few of these micronutrients that many Americans are insufficient in and are important for immune function.

We have talked in great detail about the important role vitamin D plays in preventing lung injury. So to learn more about that, go to foundmyfitness.com and search vitamin D lung injury in the search bar. I know I have said this many times, but I think it is so important for people to realize that vitamin D3 gets converted into a steroid hormone that regulates around 5% of the protein encoding human genome. Immune function is only just one very important aspect to what is actually a larger conversation around the incredibly broad role of vitamin D. Vitamin D3 is made in the skin upon UVB exposure from the sun. Anything that blocks UVB radiation from the sun also blunts our

skin's ability to produce vitamin D. That includes clothing, sunscreen, melanin, which is responsible for darker skin color, living in a northern latitude, and staying indoors. Many aspects of modern life, in a sense, are at odds with our natural production of vitamin D. This may explain why approximately 70% of the U.S. has what is called vitamin D insufficiency, while a further 28% has a low enough level to be called deficient. According to the Endocrine Society, blood levels of 25 hydroxyvitancy vitamin, D below 20 nanograms per milliliter is considered deficient and less than 30 nanograms per milliliter is considered insufficient. A meta-analysis of 25 randomized controlled trials has found

that vitamin D supplementation can decrease respiratory tract infections by more than 50% in people with vitamin D deficiency and by 10% in people that were already vitamin D sufficient. So vitamin D plays an important role in activating the innate immune system. Immune cells, have vitamin D receptors. Vitamin D activates DNA immune system, which elicits an early antiviral response. Vitamin D binds to the receptors on neutrophils, macrophages, and natural killer cells

and stimulates them to produce microbial peptides that have antiviral activity. Natural killer cells are able to induce lysis of virus-infected cells. Vitamin D also inhibits the production of pro-inflammatory cytokines, although this may seem counterproductive during a respiratory infection, the pathogenicity of viruses are also associated with what is called

hypercytokinemia or a cytokine storm, which is this potentially fatal self-perpetuating inflammatory cycle. For more information on vitamin D, please review the clip that I just mentioned on how vitamin D may prevent lung injury. Let's move on and talk about vitamin A. Vitamin A is important for the maturation and function of epithelial tissues and immune cells. Vitamin A deficiency is associated with impaired barrier function, altered immune responses, and increased susceptibility to a range of infections. Vitamin A deficient mice experience breakdown of the gut barrier and decrease mucus production, which might decrease the protective barrier and allow pathogen entry. Vitamin A controls neutrophil maturation. In vitamin A deficiency,

blood and neutrophil numbers are increased, but they have impaired phagocytic function. vitamin A supports phagocytic activity and oxidative bursts of macrophages. Vitamin A deficiency is associated with diminished natural killer cell activity, which would impair antiviral defenses. Vitamin A deficiency can impair the response to vaccination. A study in vitamin A deficient Indonesian children provided with vitamin A showed a higher antibody response to tetanus vaccination than seen in vitamin A deficient children. vitamin A deficiency predisposes to respiratory infections, diarrhea and severe measles.

Systematic reviews and meta-analysis of trials in children with vitamin A report reduced all-cause mortality and improved symptoms of acute pneumonia. A meta-analysis of 15 randomized controlled trials involving 3,021 children with pneumonia treated with vitamin A as an adjuvant therapy found that vitamin A supplementation helped to relieve clinical symptoms and shorten the length of a hospital stay. Let's move on and briefly discuss vitamin C. Immune cells actively participate in eliminating pathogens such as bacteria or viruses from the body. Vitamin C is highly concentrated in immune cells with neutrophils and leukocytes having 50 to 100 times higher vitamin C concentrations than plasma, where it serves as a potent antioxidant.

One of the early stages of the body's immune response to viral or bacterial infection involves neutrophil infiltration into an infected tissue, where the cells engulf pathogens and initiate their removal. Nutrophils generate large quantities of reactive oxygen species, but the high levels of vitamin C present in the immune cells protect them from reactive oxygen species induced DNA damage, while also promoting neutrophil function, including reactive oxygen species production. Studies in humans have also shown that vitamin C supplementation can enhance neutrophil function in young men between the ages of 18 and 30 years, as well as in older women, average age of around 72 years. Vitamin C also appears to boost the immune system by promoting the proliferation of

T cells and preventing T cell death. T cells play a major role in driving an immune response against pathogens such as bacteria or viruses. Vitamin C also participates in the production of interferon in mice. Interferon is a type of cytokine that signals the body to initiate antiviral defenses. To learn more about the role of vitamin C in common coals and other aspects of human health, please listen or view our podcast on vitamin C. You can find that at foundmyfitness.com forward slash episodes. Let's move on and talk about zinc. The RDA for zinc is 11 milligrams per day for adult males and 9 milligrams a day for females. Approximately 8% of the U.S. population has inadequate zinc intake and up to 45% of people 60 and older have inadequate zinc intake.

Zinc deficiency in the U.S. is rare. People that consume alcohol or are vegetarian may require more zinc. Alcohol increases zinc excretion by 50%. Vegetarians are getting their zinc from plant sources which has zinc bound to phytate and lowers its bioavailability. Vegetarians are getting their zinc from plant sources, which has zinc bound to phytate and lowers bioavailability. Vegetarians may need to consume up to 50% more of the RDA for zinc in order to get adequate levels. Zinc has been shown to play a role in pneumonia. A randomized controlled trial in about 600 elderly individuals given a multivitamin that contained zinc for one year, found those individuals with the highest zinc levels after supplementation were almost 50% less likely to get

pneumonia. Another randomized control trial and hospitalized children found that 20 milligrams of zinc per day reduced pneumonia symptoms by 30% compared to a placebo. A meta-analysis of six randomized controlled trials found that zinc supplementation in children reduced pneumonia prevalence by 41%. Zinc has also been shown to play a role in the common cold. A meta-analysis of three trials found that supplementation with zinc acetate lozenges around 80 to 90 milligrams, a day found that they had a threefold faster recovery rate from the common cold compared to a placebo. Another meta-analysis of seven separate trials using either zinc acetate or zinc gluconate lozenges found they reduced the common cold duration by 33% compared to placebo.

Doses lower than 75 milligrams per day have not been shown to have an effect on the common cold. So let's touch a little bit on zinc and immune function. Studies have shown that mild zinc, Dink deficiency may decrease immune function, including dysfunctional cytokine production in T cells, and regeneration not occurring in CD4 positive T cells. Multiple in vitro studies have found that zinc inhibits the replication of RNA viruses. But this is in vitro. Zinc is a positively charged ion, so it cannot get into the cell without a transporter. But there is another way that zinc can get into the cell without a transporter.

A zinc ionophore can help transport zinc across the cell plasma membrane, and this can help zinc get into the cell. Let's move on to the last part of this section on nutrition and talk about omega-3 fatty acids. The omega-3 fatty acids, EPA and DHA support an effective immune system by helping to resolve the inflammatory response after the infection. Inflammation, a key part of the immune response, is an influx of fluid, immune cells, and other mediators that function to eliminate the infection. After the immune response, the omega-3 fatty acids, EPA and DHA present at the inflammation site are enzymatically converted to specialized pro-resolving mediators, known as resolvins, protectins, and meresins. These molecules, along with others, function together to orchestrate

the resolution of inflammation and to support healing, including in the respiratory track. Nutritional deficiencies in these essential fatty acids can result in delayed or suboptimal resolution of inflammation. This could be very important in the context of a cytokine storm, linked with acute respiratory distress syndrome. In animal models, specialized pro-resolving mediators formed from EPA and DHA have been shown to both protect against and resolve acute lung injury and acute respiratory distress syndrome. Gender may also play a role in differences in immune response. Women have better immune responses to vaccinations than men possibly due to the fact that estrogen

is an enhancer of the humoral immunity, whereas testosterone is a suppressor. Animal studies have shown that female mice are more protected from influenza compared to male mice, but when given estrogen blockers, female mice had the same death rate as male mice. Estrogen promotes adaptive T-cell responses in female mice by increasing neutrophil accumulation. Additionally, estrogen signaling limited influenza virus replication in nasal epithelial cells. Animal studies have shown that male mice are more likely to die from SARS-Cove 1 than female mice. With respect to COVID-19, data suggests that men and women are equally likely to get the disease, but that men are more likely to die from it. Of 168 Wuhan patients who died from SARS-CoV-2,

75% of them were male. Similar trends have also been seen in South Korea and Italy. Another factor may be that men have less ACE2 receptor because the receptor is increased in the presence of estrogen. What is interesting is that even though men are dying more often, the gender split for infections is around 50-50. This means the cause of increased mortality is not due to risk factors for contracting infection, meaning that men are not dying more because they are exposed more, wash their hands less, or are less likely to go to the hospital. The differences of mortality may boil down to how sex hormones differentially affect the immune system. Let's talk briefly about biological age. Science has shown us that the way people age is very

different starting in early life before any diseases are present. For example, in a population of about 1,000 people who had their physiology studied from birth until the age of 38, the data showed that they aged at very different rates. In other words, people with the same chronological age may have a vastly different biological age because of combined genetic and lifestyle factors. Some people may have a younger chronological age, but an older biological age, and vice versa. data looking at responses to vaccines seem to suggest that biological age was a predictor of a better immune response. All in all, there are likely many factors that play a role in the variability in immune responses between different otherwise healthy individuals. Let's move on to the next question.

Several articles mentioned possible higher risk among people who take ACE inhibitors or ARBs for hypertension. Is there actually a higher risk? has this been tested. Let's start with a brief overview of the ACE receptor with respect to Sargecove 2. The Sargecove 2 virus attaches to the ACE2 receptor in order to infect a cell. Cells that lack ACE2 do not get infected with the virus. Ace 2, also known as angiotensin converting enzyme 2, is an enzyme found throughout the body to counteract the action of ACE1 in the reen and angiotensin system. Together, ACE 1 and ACE2 function to regulate blood pressure and salt balance. Ace 1, ACE2, ACE2,

imbalances such as higher ACE1 or lower ACE2 are seen in many disease processes such as atherosclerosis, high blood pressure, heart failure, chronic kidney disease, inflammation, and lung injury. When SARS-CoV-2 virus enters human cells via the ACE-2 receptor, the ACE-2 receptor is internalized into the cell with the virus. This results in a decrease of the number of functioning ACE-2 receptors and worse disease severity. This has been shown to occur with the original SARS-Cube COVID-1 virus. The decrease in ACE2, coupled with the cytokine storm, creates a vicious inflammatory milieu, which can spiral out of control and lead to acute respiratory distress syndrome. This is supported by data from animal studies where acute lung injury decreases ACE2

receptor levels, and this exacerbates disease severity. But vitamin D increases ACE2 levels, and this was shown to protect against acute lung injury. In short, ACE2 is a key protective factor for severity of lung edema and acute lung failure. The epidemiology of COVID-19 also supports this. Those with decreased ACE2 levels are also those who have been seen to have more severe COVID-19 cases. This includes people with chronic diseases, elderly, and males. It has been hypothesized that since ACE inhibitors and ARBs, which are angiotensin-2 receptor blockers, Increased ACE2, they may reduce the risk of severe disease in these populations that are at risk.

Several cardiovascular societies have recommended continuing taking ACEs and ARBs. They argue that the increased protection from severe disease, the ACEs and ARBs could provide is worth a theoretical tradeoff of increased risk of infection. In fact, there is a paper suggesting that ARBs should be used to treat COVID-19. A case population study from Madrid involving 1,139 cases and 11,390 control subjects, assessed whether anti-hypertensive drugs affect the risk of contracting COVID-19 requiring hospitalization. Compared to the other hypertensive drugs, RAS inhibitors such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers,

which increased ACE2 receptor levels, were not associated with an increased risk of COVID-19 requiring admission to the hospital. In fact, patients with diabetes taking these inhibitors had a decreased risk of COVID-19 requiring admission to the hospital, suggesting a possible decrease in disease severity. But more data is needed and only time will tell. Let's move on to the next question. Does COVID-19 cause irreversible damage to the lungs? complications from severe COVID-19 such as pneumonia and acute respiratory distress syndrome can lead

to irreversible damage. In patients with acute respiratory distress syndrome, fluid leaks into tiny air sacs in the lungs and prevents air exchange. Acute respiratory distress syndrome can lead to pulmonary fibrosis, which is a buildup of scar tissue in the lungs, decreased quality of life and potentially death. Patients that develop acute respiratory distress syndrome, from SARS-Cove 2 are much more likely to die. In 191 confirmed coronavirus patients in Yuhuahan, researchers found 50 of 54 patients who died had developed acute respiratory distress syndrome, while only nine of the 137 survivors had acute respiratory distress syndrome. Survivors of acute respiratory distress syndrome are not out of the woods yet, though,

because they have long-term long damage, which may lead to a decrease in quality of life. A cohort study of 50 acute respiratory distress syndrome survivors found that five and a half years post-discharge from the ICU, the survivors had a 25% reduction in physical function compared to controls as measured by health-related quality of life assessment. Another study that followed 109 survivors of acute respiratory distress syndrome for up to five years also saw a decrease in quality of life. At five years after recovery, the distance that survivors could walk in six minutes had decreased by 24%. Both young and older patients had reduced physical capabilities

compared to before, but younger patients had less of a loss. Older patients hospitalized for pneumonia are significantly more likely to have cardiovascular disease. One large observational study followed 591 pneumonia patients for up to 21 years. The risk for cardiovascular events was four times higher in the first 30 days after pneumonia and 1.5 times higher in the subsequent years. Fortunately, patients that do not develop pneumonia or acute respiratory distress syndrome do not appear to have irreversible damage, but long-term data specific to COVID-19 is not available yet and only time will tell. That's it for this special edition, round two COVID-19 Q&A. Thanks so much for listening and watching. During the genetic section of this podcast, we discussed a variety of

SNPs that affect viral entry into the host cell, viral replication, host immune response, ranging from cytokine production to viral induced inflammation, snips that affect the vitamin D levels, and more. If you have used any consumer-based genetic testing services like 23Mee or Ancestry DNA, we have a free viral report with these SNPs that you can check out. You can find that at foundmyfitness.com forward slash genetics. Talk to you soon.