What Does Long-Covid Have In Common With Diabetes, arthritis, and Depression?
Extending Our Understanding of How Chronic Inflammation Drives Common Illnesses to Include Long-Covid
I. Introduction
In the last two Briefings, evidence was presented that causally links chronic low-grade generalized inflammation (CGLI) precipitated by obesity and/or psycho-emotional stress, to various common diseases including osteoarthritis (OA), type-II diabetes (T2D), cardiovascular, liver, and kidney disease, as well as major depressive disorder (MDD).
In each of these chronic illnesses, ‘hormones of the immune system’ known as inflammatory cytokines act on a class of white blood cells called monocytes to up-regulate their genetic expression of a type of enzyme that breaks down protein, called matrix metalloproteinase (MMP).
Each of our bodies’ organs has a distinctive shape, color, and texture, as determined by their own unique protein-rich extracellular matrix (ECM) that not only gives structural form and support to the organ but also helps facilitate and coordinate local tissue biochemical (and mechanical) processes that enable it to do its job properly.
The main job of MMPs is to break down the protein-rich ECM. This is critically important for building new blood vessels (angiogenesis) and clearing away damaged tissues to pave the way for cellular repair and subsequent tissue remodeling after an injury or infection. In the brain, MMPs also play an essential role in neuroplasticity — the ability of nerves to break old connections and form new ones, which is how we learn and store memories. Finally, MMPs help clear away cells that grow old and sick (cellular senescence), enabling fresh new cells to take their place through a process known as apoptosis, which is part of how our immune systems protect us from cancers.
MMPs and TIMPs
So, MMP is an important element in immunity and homeostasis (the steady state of internal biochemical and physical balance maintained by living systems to provide optimal conditions for functioning). At any given time, the ECM of a healthy organ contains both MMPs and also another class of hormones that act to tamp down the action of MMP, called tissue inhibitors of MMPs or TIMPs. These oppositional actors (MMPs and TIMPs) exist in a dynamic tension designed to maintain homeostasis.
During an injury or infection, an acute inflammatory response occurs that significantly upregulates MMP production and suppresses TIMPs to induce the breaking down and clearing away of damaged/infected tissues. As the acute inflammatory response recedes (after the infection or toxin has been cleared, for example), TIMP is then up-regulated to block the catabolic (breaking down) action of MMP and initiate the anabolic (building up) process of tissue repair and remodeling.
Homeostatic immunity involves briefly tilting the tug-of-war catabolically in favor of MMP during infection and then tilting it the other way, anabolically, in favor of TIMP after the infection has been cleared. Ideally, both of these tilts are short-lived, and a balanced dynamic tension between MMPs and TIMPs is restored after a few days or a few weeks.
However, this homeostatic balancing act can go awry when CLGI persists for months or years in someone who is obese or whose life includes too high levels of daily stress. Chronic inflammation tilts the balance of hormone expression steadily in favor of MMP, driving a slowly progressive (catabolic) erosion of the ECM. Over time, this leads to the destruction of vital structural and functional tissues within the organ, followed by scarring and eventually, fibrosis.
When these pathological processes take place in joints, we call it OA. In adipose tissue, we call it T2D. In the liver, we call it cirrhosis. In lung tissue, we call it pulmonary fibrosis. And, when MMPs degrade the matrix in the brain's reward centers such as the nucleus accumbens, the result is major depression (MDD). Now, new information is pointing to yet another CLGI/MMP-driven chronic disease: long-covid (LC).
II. Cognitive Impairment After COVID-19 (C-19)
Chronic Disability, not Hospitalizations and Deaths, is the Worry
‘Brain fog’ describes a chronic impairment of attention, memory, information processing speed, and the ability to multitask. It is one of the most common symptoms associated with long-covid (LC), often (but not always) seen accompanied by chronic fatigue. Brain fog had been well-described before the pandemic, associated with a handful of other infections, including mono (infectious mononucleosis) and Lyme disease. But it happens at a higher rate after C-19, with an estimated million-plus adults in the US having developed brain fog during the pandemic.
The majority of Americans with LC brain fog are young adults in their twenties, thirties, and forties, with a growing share in their teens. A systematic review showed that up to 50% of children who get C-19 progress to LC and in a review of eighteen studies that followed patients for at least one year after a C-19 diagnosis, 28% were still reporting fatigue/weakness, 18% had difficulty breathing, 26% had body aches, 23% had depression or anxiety, 19% had memory loss, and 18% still had difficulty concentrating at least one year after their acute infections.
It seems fair to say that for young, otherwise healthy people, the most concerning risk posed by C-19 is not hospitalization or death which occur almost exclusively among older adults and/or those with serious concurrent health problems such heart disease and diabetes. Rather, it is developing LC and/or post-covid conditions (PCCs).
This was one of the many nuanced understandings that were, in my view, poorly communicated by our premier public health organizations during the pandemic. Why, many wondered, would anyone think it is a good idea to mandate masking in or closures of schools when the C-19 virus rarely sends kids to the hospital? We do not yet know how many children will suffer years (or perhaps a lifetime) of disability after a ‘mild’ case of C-19. Erring on the side of caution to lower the risk of long-term problems like brain fog may or may not have been the right call. Only time will tell. But the refusal or inability of public health experts to convey this somewhat nuanced understanding of how C-19 affects young people certainly played, in my view, at least some role in the rancorous divide those recommendations caused.
Long-Covid (LC) and Post-Covid Conditions (PCCs)
LC describes symptoms that come on during or immediately after the acute infection, most commonly brain fog, chronic fatigue, shortness of breath, and loss of smell, which can persist for weeks, months, or years. In addition, it is now well-established that the risk of developing any number of common chronic diseases goes up significantly in the weeks and months after C-19. Diseases that seem to have been induced by a C-19 infection are referred to as post-Covid conditions (PCCs).
Clotting problems that can cause strokes and heart attacks, autoimmune diseases, T2D, infertility, kidney disease, depression, anxiety, and a host of other serious health conditions become significantly more common after C19 — even among those who were not at high risk before getting infected and had only a mild acute infection that felt like a slight cold. These PCCs now make up a significant share of the disease burden in the US, with about 15 - 20% of American adults having experienced LC or a PCC, according to the CDC.
Diabetes as an Example
T2D is one of the many common PCCs. SARS-CoV-2, the virus that causes C-19, can directly infect the cells in the pancreas that make insulin, known as beta cells. Infected beta cells may become chronically debilitated after C-19, limiting their ability to secrete insulin which can lead to diabetes. But another possible mechanism for post-C-19 T2D (and one that is particularly germane to this discussion) is that chronic inflammation triggered by the virus drives insulin resistance. It is estimated that the risk of developing T2D goes up by about 60 - 70% after C-19 according to a recent meta-analysis.
Chronic inflammation after C-19 seems to be triggering a whole host of serious health problems that extend well beyond diabetes. SARS-CoV-2 can directly infect the endothelial cells of arteries, including coronary arteries and cerebral arteries, and the inflammation that infections of these cells provoke can result in clots that lead to heart attacks and strokes. Young people between the ages of 25 - 44 saw a 30% increase in heart attack deaths in the first two years of the pandemic. I will say more about this later but for now, let’s just make a note that LC and PCCs are common after C-19 and that chronic inflammation seems to be a critical part of what’s driving the problem.
III. The Brain: C-19, Microglia and the Perineuronal Net
Direct Infection
SARS-CoV-2 can make its way into the brain through the olfactory nerve, whose receptors carry the sensation of smell from the nose to an area of the cerebral cortex that deals not only with olfactory perception but also with memory. One major study conducted in the UK compared MRI brain scans of people before and after the start of the pandemic and found that the area of the brain that deals with smell and memory had been damaged or destroyed in a high percentage of people who had been infected compared to no changes on follow-up scans among those who had never had C-19.
It is also believed that the virus can enter the brain through leaks in something called the blood-brain barrier (BBB). Arteries, including the small vessels that supply blood to the brain, are lined with a kind of cellular filter called the endothelium. Endothelial cells are packed tightly together to form a barrier that prevents things floating around in the blood from inadvertently entering the tissues of the brain. Normally, these 'tight junctions’ between endothelial cells allow only very small (molecular-sized) particles like oxygen and glucose to slip through the cracks where they are taken up as nutrients by brain cells. However, as mentioned earlier, SARS-CoV-2 can infect endothelial cells, damaging them and making those tight junctions looser. Infection of endothelial cells in the small blood vessels of the brain can lead to clots (thrombi) and strokes. Widening the gaps between endothelial cells after they are damaged by infection allows larger particles coursing through the bloodstream, including the virus itself, to make their way into the brain.
Microglia
When the virus gets into the brain, it triggers a cascade of inflammatory responses that up-regulate the expression of MMP. SARS-CoV-2 (especially, it seems, the virus’ spike protein) is an especially provocative invader, capable of causing a particular type of immune cell found only in the ECM of the nervous system, called microglia, to malfunction. Microglia are part of the brain’s innate immune system. They help clear away toxins and fight off infections. They also play an important role in regulating and remodeling the nervous system’s ECM.
One of the many ways in which SARS-CoV-2 seems to be different from most other human viruses is that it provokes an unusually powerful and sometimes chaotic immune response. This was widely described in the early days of the pandemic as a ‘cytokine storm,’ and we are now seeing that the direct immune challenge to brain cells (especially microglial cells) caused by the virus can induce a kind of chronic immune hyperreactivity to the virus’ spike protein.
This hyperreactivity can induce autoimmunity disease in some (through a process known as antigenic mimicry in which regions of the virus that are similar to the body’s own proteins are targeted for destruction and the immune system begins to mistakenly attack normal healthy tissues containing that similar protein). It can also cause the microglia to become so hyper-focused on the virus that they stop attending properly to their other important homeostatic functions.
The Perineuronal Net (PNN)
So SARS-CoV-2 dysregulates the brain’s immune system by inducing inflammation that makes microglial cells hyperreactive to and hyper-focused on the virus’s spike protein. This inflammation up-regulates the production of MMP — in this case, not by monocytes but by microglial cells — which degrades proteinaceous components of the brain’s ECM (such as collagen, fibronectin, and elastin). In addition, SARS-CoV-2 also dysregulates other important brain tissue cells such as oligodendrocytes and astrocytes which provide structural support to part of the brain’s ECM known as the perineuronal net (PNN).
The PNN is a mesh-like connective tissue structure that wraps around brain cells (neurons). It is part of the extracellular matrix (ECM) and is involved in the development and function of neurons, including neural plasticity which, as mentioned earlier, is essential for learning, memory, and cognition. Disrupting synaptic neural plasticity by damaging the PNN through the upregulation of MMP by microglia explains well the brain fog commonly seen among patients with LC.
IV. Chronic Viruses Cause CLGI and CLGI Causes Chronic Illness By Upregulating MMP
Recent studies have shown increased MMP levels (especially MMP-3 and MMP-9) in the blood of patients with mild, moderate, and severe C-19, especially among those with comorbidities like T2D, and suggest that the degree to which MMP is up-regulated can be used as a biomarker for disease severity, with serum levels of MMPs significantly tethered to the disease stage.
When challenged immunologically by the virus’s spike protein, microglia up-regulate their expression of MMPs, especially MMP-9. Elevated MMP-9 has been documented within the central nervous system’s cerebrospinal fluid, heart muscle cells (myocardium), and other organ tissue cells, during and after C-19.
Research is now pointing toward an understanding that microglial hyperreactivity triggered by C-19 infections can occur even when the virus doesn’t make its way physically into the brain. It appears that the inflammatory changes in the respiratory system and elsewhere in the body can trigger this reaction through excessive production of inflammatory cytokines which become systemic. If this systemic inflammatory response becomes chronic, post-infection CGLI can dysregulate the balance between MMPs and TIMPs leading to the destruction of elements of the brain’s ECM, including the PNN.
Chronic Viruses
Some viruses can embed themselves in the human body, taking up residence within immune hubs like lymph nodes, bone marrow, white blood cells, the spleen, and other tissues like nerve cells (neurons). Herpes Simplex is a common virus that infects up to 80% of people; Epstein-Barr virus (EBV) is estimated to infect up to 95% of people. For most of us, these chronic viruses live inside of our bodies, lying dormant for weeks, months, or years, kept in check by our immune systems, and can be activated to cause illness by stress, injury, or infection.
It now appears that SARS-CoV-2 may, in some, be another chronic virus that can persist in the body for long periods. At the 31st Conference on Retroviruses and Opportunistic Infections (CROI), held earlier this month, researchers from UCSF presented data from 171 patients showing that the virus (or parts of the virus) can persist in the blood, lymph, bone marrow, and other tissues for more than two years in patients following C-19.
The persistence of certain chronic viruses in so-called viral reservoirs has been well documented. Viral RNA from the Ebola virus has been found in breast milk, semen, and ocular fluid months or years after the primary infection. Zika virus has been shown to persist in body fluids for years. And measles virus can be found in various body tissues months or years after the initial infection.
These viral reservoirs have been demonstrated to drive relapses of infectious illness as well as CGLI and symptoms of chronic disease including brain fog. It has also now been well documented that SARS-CoV-2 can persist in serum, brain, lung, gut, nose, throat, and various other body tissues. When the immune systems of the body, including the microglia in the immune system of the central nervous system, become overly focused on fighting the persistent presence of SARS-CoV-2, they can, in effect, take their eyes off of preexisting chronic infections like EBV (the virus that causes mono), herpes simplex, and varicella-zoster (the virus that causes both chickenpox and shingles), triggering relapses of those viral illnesses — something that has been widely observed after both infections and vaccination against C-19. One study estimated that patients were twice as likely to get shingles in the weeks and months after C-19.
In short, one of the major theories of LC involves the persistence of SARS-CoV-2 in viral reservoirs where it induces a state of CGLI that can trigger PCCs and relapses of other chronic viruses.
V. Cancer Therapies and Brain Fog
The cognitive impairment commonly known as brain fog, well-described in the context of certain chronic viruses, is also seen in response to cancer therapies, including chemotherapy, radiation, and immunotherapy, one side effect of which is microglial malfunction. Brain microglia, induced into a state of chronically dysregulated hyperreactivity and over-expression of MMP by an ongoing toxic immune challenge among patients undergoing cancer therapies, is now informing the most current understanding of LC and PCCs.
Among those leading that charge is Dr. Michelle Monje, a physician and research scientist who specializes in the care of a rare and lethal form of pediatric brain tumor. Dr. Monje was the guest of Dr. Eric Topol in a recent edition of Ground Truths, published here on Substack. In this interview, she lays out in detail the latest understanding that links radiation, immune, and chemotherapy-induced cognitive impairment, as supported by preclinical models in the laboratory and confirmed by human tissue studies, to microglial dysfunction, destruction of the brain’s ECM, and atrophy in the same areas of the brain that are affected by C-19.
I strongly recommend subscribing to Dr. Topol’s podcast where he hosts some of the best minds in the world and presents some of the most cutting-edge data and ideas impacting medicine and AI.
VI. OA, T2D, heart, liver, and kidney disease, MDD, and now, LC and PCCs
It is becoming clear that the degradation of the ECM caused by upregulated MMP, driven by CGLI, leads to organ injury and eventually, chronic diseases of various kinds, including arthritis, diabetes, heart attacks, strokes, autoimmune diseases, and depression.
What also seems to be emerging from the most current research is the understanding that chronic inflammation and dysregulated microglial immunity within the brain, either in response to direct infection or through the action of CLGI in response to the persistence of SARS-CoV-2 in viral reservoirs, degrades the ECM of brain tissues in the areas of smell, memory, and cognition through the persistent upregulation of MMP-9. These findings fit well with the symptoms of LC, especially brain fog, and offer a theoretical basis for understanding a problem now estimated to be affecting more than a million adults following C-19.