April 2nd, 2020
Warning - very technical piece. However, it explains a lot about risk and lifestyle choices mechanistically. We are learning a lot rapidly. There is no time to waste to reduce your risk and be a part of the 99%.
As we looked at last week, prevention of a bad outcome, death, through lifestyle modification is imperative for our health as it relates to SARS2. After looking at ways to support the immune system through lifestyle choices and some targeted supplements, this week we are going to go a lot deeper into the science behind the immunology of the inflammatory response that is driving disease that we see as ARDS or adult respiratory distress syndrome and multi organ failure.
Remember from earlier posts that the SARS2 virus enters the lungs via the type 2 pneumocyte and an angiotensin converting enzyme receptor.
The virus binds to the ACE receptor gaining access to the lung tissue. The alveolus (picture link) is an air sac in the terminal lung tissue that expands with respiration to exchange oxygen and carbon dioxide with the blood. The type 2 pneumocyte sits inside of the alveolus and releases a chemical phospholipid called surfactant that holds the alveolus open by reducing surface tension avoiding collapse.
Once the SARS2 virus has grabbed the ACE receptor it fuses with the cell and injects its RNA genome inside the cell. It then begins to replicate rapidly in these cells which can ultimately destroy the lung alveoli's capabilities by reducing the production of surfactant in these type 2 pneumocytes. These same cells would normally produce angiotensin converting enzyme 2, ACE2, that is normally lung protective and anti-inflammatory and reduced in this infection serving as a double whammy at the lung tissue site. This is the beginning process of what we see of as ARDS. When enough of these small air sacs collapse, air exchange becomes impossible and patients respond by increasing the rate of breathing and using accessory muscles to draw deeper and deeper breaths until this is not enough to maintain oxygen levels. Essentially, your lungs collapse to the point that effective oxygen exchange is lost and life is not sustainable without mechanical ventilation. If the inflammation and organ damage worsens, then that may not be enough and death ensues.
See Figure 2 here for a pictorial of the etiology of the pathogenesis.
The other big problem in this infection is that the SARS2 virus has the ability to infect or enter immune cells causing a rapid decline in white blood cell function and a corresponding extraordinary release of chemicals called cytokines that inflame all local tissues worsening the disease in multiple organs.
From a recent article on SARS2 pathogenesis: "Based on the published literature and clinical observations of COVID-19 patients, we propose reasonable hypotheses about the pathogenesis of SARS-CoV-2 infection in humans. The virus might pass through the mucous membranes, especially nasal and larynx mucosa, then enters the lungs through the respiratory tract. The early most common symptoms of infection are fever and cough. The virus may enter the peripheral blood from the lungs, causing viremia. Then the virus would attack the targeting organs that express ACE2, such as the lungs, heart, renal, gastrointestinal tract. The SARS-CoV-2 detected in the fecal samples is more likely because the virus enters the blood from the lungs and then travels from the blood to the intestines, which supports our hypothesis. Dawei Wang et al found that the median time from symptom onset to ARDS was about 8 days. We speculate that in this way, the virus begins a second attack, causing the patient's condition to aggravate around 7-14 days after onset. During the infection process, the white blood cell count in peripheral blood in the early stage of the disease is normal or slightly low, and lymphopenia is observed in patients. We speculate that B lymphocyte reduction may occur early in the disease, which may affect antibody production in the patient. In severe type patients, lymphocytes were significantly reduced. We speculate that lymphocytes in patients with COVID-19 might gradually decrease as the disease progress. But the mechanism of significant lymphocyte reduction in severe type patients remains unclear. Besides, the inflammatory factors associated with diseases mainly containing IL-6 were significantly increased, which also contributed to the aggravation of the disease around 7-14 days after onset. Non-survivors had higher levels of neutrophils, D-Dimer, blood urea nitrogen, and creatinine than the survivors. " (Lin et. al. 2020)
Understanding the pathogenesis of the virus is key to making educated choices to support immune responses. The bottom line according to the excellent work by Dr. Sam Yanuck is two fold with regard to prevention of SARS2. First, support immune surveillance by making sure that the immune system is fine tuned to recognize and destroy the virus early on so that it has minimal opportunity to replicate and hijack our immune system. Secondly, support survival if you get ill and the virus has had the ability to replicate. This means that we want adequate and functional responses from natural killer cells and T helper type 1 cells. Then you need a low starting inflammation point so that when your immune system begins to inflame and attack the virus, you are not pushed into a place of over inflammation and death. (again from earlier posts, this is the likely etiology behind the increased death risk from diabetes, obesity, hypertension and metabolic diseases)
Directly from my colleague Dr. Yanuck, "When you support NK cell function and support Th1 response, you make more interferon gamma, which helps you inhibit Th17 cells, which quiets STAT3 and reduces Th17 cytokines. Now, none of those elements is inherently bad. They can just get out of balance.
Now, if the level of inflammation starts to get too high, your Th1 response might get you into trouble, so you have to support a reduction of inflammation. Glutathione is very important there, as the amount of gsh in the lung ELF will greatly influence extent of inflammation.
Now, one of the key things that can be most important in giving you a low starting level of inflammation is the extent of expression of inflammasome NLRP3. Look at the data on inflammasomes and autoinflammatory diseases. This is a class of diseases involving overactivation of the innate immune system.
Inhibitors of inflammasome activity are: resveratrol, quercetin, berberine (via promotion of AMPK), potassium (don't overdo it, just be sure they're not below 4.0), reducers of ROS like sulforaphane (ROS inhibit SIRT2, and SIRT2 blocks inflammasome assembly), caloric restriction (by increasing NAD). Things that increase inflammasome activity: poor glucose control, low serum pH, high fatty acid levels, uric acid, etc." (Yanuck S. 2020)
Inflammasomes are a significant part of our innate immune system and unfortunately play a large roll in the SARS2/COVID disease pathogenesis. (Chen et. al. 2019) They form in response to perturbations in the balance of system functions whether through a pathogen exposure like a pathogen associated molecular peptide of a bacteria or virus or excessive nutrient intake as in obesity or cholesterol crystals or environmental toxicants and so much more. If the perturbation resolves, then the inflammasome resolves. If not, .... then not. For example, if you consume a poor quality standard American pro inflammatory diet, then you will randomly trigger inflammasome activity in your body on a chronic scale which will increase the release of interleukin 1beta, IL1B, which is a super potent inflammatory cytokine. This cytokine is a signaling molecule that locally causes a fire in an effort to respond to the stress. If the stress is persistent dietary choice, you will have a persistent fire. There are also huge shifts in IL6, IL8 and TNFa further inflaming the system. (Totura et. al. 2012) Usually gamma interferon is present in adequate quantities to quell the over reaction. In SARS cases that have poor outcomes, the interferon response is not adequate making a genetic risk likely in some populations. (Totura et. al. 2012)
Now, we know that obesity and type 2 diabetes are risk factors for a negative COVID outcome. We also know that obesity and type 2 diabetes are associated with significant flares in inflammasome activity. Therefore, the leap of faith seems to be that if we reduce the triggers of baseline inflammasome activity, then we could mitigate some of the downstream risk if we contract SARS2.
When we look at this last section, we see major issues that can be driven by poor quality food choices. For example, high fructose corn syrup is metabolized to extra uric acid a known trigger of inflammasome formation. Refined foods are loaded with poor quality fatty acids and huge glucose loads that drive inflammasome responses and suppress Th 1 and NK cell activity. Corn fed animal meats are loaded with pro-inflammatory omega 6 fatty acids that are potentially driving the excessive arachidonic acid and cytokine response. These events conspire to reduce viral surveillance and killing while paradoxically increasing inflammation through inflammasome formation and cytokine release. This is the perfect storm for a bad outcome.
I truly think that this virus is a wake up call for all of us to eat whole foods that are minimally processed, mostly vegetables, fruits, legumes, seeds and nuts spiked with wild caught naturally raised meat, fish and eggs. That is a dramatic recipe for inflammasome reduction and protection.
For a final point of understanding - there is a disorder called CAPS or cryopyrin associated periodic fever syndrome that is a genetic defect in the NLRP3 inflammasome. It causes severe fevers, rashes, joint pain and swelling, brain inflammation and can lead to death at a young age. This genetic disorder is the poster child for why you do not want an over acitve NLRP3 inflammasome. Practice lifestyle medicine and reduce your risks to SARS2!
Thank you for bearing with me through that deep dive into immunology. I hope that it helps explain the WHY we need to be proactive with lifestyle medicine and nutritional therapy.