Long COVID: Immune and Systemic Effects of Post-Viral Infection Part II: Ongoing Inflammation and Autoimmunity

In the first part of this series on post-COVID illness, I reviewed some of the issues of post-viral syndromes and their relationship to the current pandemic with a deeper look into the effects of SARS-CoV-2 on the nervous system. Many of the symptoms associated with long COVID present as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with some additional symptoms specifically associated with COVID-19. Post-viral syndromes are not new, but it is not completely clear as to why some patients experience lasting symptoms after a viral infection and some do not. We do know that immune system activation by a virus increases systemic inflammation, oxidative stress, and tissue damage. We also know that our genetics play a role, as evidenced by the tendency to develop autoimmune conditions for those with specific human leukocyte antigen (HLA) phenotypes that can be triggered by certain infections. The tendency to develop ongoing inflammation and lingering symptoms after an infection might be relative to baseline inflammation and immune system balance upon encountering the virus. The potential to unmask underlying chronic infections may also contribute to the symptoms of long COVID. We are all exposed to viruses and other infectious agents throughout our lifetime that can exist in a latent state only to reactivate during a time of stress and immune dysregulation, which adds to the complexity of post-viral syndromes including long COVID.

SARS-CoV-2 and the Immune System

Viruses have evolved to evade the immune system in many ways. SARS-CoV-2 disables the innate immune system during early infection by blocking the ability of Toll-like receptors (TLR) to signal the production of interferon-I (IFN-I), which is crucial for reducing viral replication and spread [1,2,3]. This gives the virus a greater chance to replicate during early infection, leading to higher viral titers and the potential for a heightened inflammatory reaction later. Innate immune response during early infection determines what will happen later in the disease process and possibly beyond recovery from the acute infection. Reducing viral load early may decrease the chance of continued inflammation, autoimmunity, and poor viral clearance.

In a mouse model of SARS-CoV-2 infection, local IFN responses in the lungs were delayed relative to peak viral replication, which greatly reduced viral clearance and was associated with the development of cytokine release syndrome (CRS) [1]. Through various mechanisms, coronaviruses are known to inhibit the early production of IFN but increase the production of nuclear factor kappa light chain enhancer of activated B cells (NF-KB), resulting in production of inflammatory cytokines and chemokines. IFN acts as a central liaison between the innate and adaptive immune systems and signaling can trigger various messages that dictate how and when the innate and adaptive immune systems respond to viral infection.

Use of INF during early infection has shown some promise to reduce viral replication; however, the timing of use is critical. Introducing INF too late in the disease process may result in a heightened inflammatory response that may contribute to the development of a cytokine storm and interfere with effective recovery [1]. Given the safety concerns regarding the use of IFN as a treatment option for COVID-19, considering nutraceuticals that can boost IFN-I might be a better option. McCarty et al identify key mechanisms of action of ferulic or lipoic acid, spirulina, N-acetyl cysteine (NAC), selenium, glucosamine, zinc, beta-glucan, and elderberry, which can interfere with the ability of the virus to inhibit IFN-I through support of TLR activity and boosting of IFN-I production [2].  We are familiar with most of these nutraceuticals as immune system support and specific dosages are highlighted in the article.

Recent studies out of Casanova’s lab at The Rockefeller University have also discovered the relationship between genetic mutations and inborn errors of IFN-I immunity and the severity of COVID-19. They have also noted some patients with severe COVID-19 can develop autoantibodies to IFN-I [4]. With a reduction in IFN-I activity whether through viral inhibition, genetic predisposition or the production of autoantibodies, the net effect is an increase in viral replication in the early phase of disease, which can have the effect of inducing an overly robust inflammatory reaction as the viral load increases. This overreaction may induce autoimmunity and/or chronic inflammation through bystander activation.

Immune System Dysregulation/Autoimmunity


There are three ways that a virus might induce autoimmunity: molecular mimicry, bystander activation, and viral persistence. Molecular mimicry between a virus or other pathogen and host proteins can lead to immunological cross-reactivity and subsequent attack on self. As stated in the Journal of Translational Autoimmunity, the existence of homology (molecular mimicry) between viral and human proteins is well-established in viral- or vaccine-induced autoimmunity [5]. As the body induces an immune response to the viral proteins, it also attacks similar proteins within body tissues that can extend beyond the initial infection, inciting ongoing inflammatory reactions in various tissues. The infection may have resolved; however, the inflammatory trigger is ongoing because the presence of the virus woke up the immune system in a way that initiated a reaction to proteins that were similar within the virus and within self. Much of this reaction is determined by the genetics, which is why people react differently to viruses and other pathogens. Some may recover without long-term sequelae while others battle ongoing symptoms after the acute infection.

To highlight the potential issue of molecular mimicry and SARS-CoV-2, a recent article in Clinical Immunology by Aristo Vojdani, PhD, MSc, CLS, and Datis Kharrazian, PhD, DHSc, DC, MS, MMSc, FACN, examined cross-reactivity of viral antibodies with various body tissues. They tested five different blood specimens confirmed positive for SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies for anti-nuclear antibody (ANA), anti-extractable nuclear antigen (anti-ENA), anti-double stranded DNA, actin antibody, mitochondrial antibody, rheumatoid factor, and complement component 1q immune complexes. Three of the five specimens had elevated ANA, anti-ENA, actin, and mitochondrial antibodies. Further studies revealed 21 out of 50 tissue antigens reacted with the SARS-CoV-2 antibodies, indicating a cross-reaction between SARS-CoV-2 proteins and several tissue proteins. These tissues included the lungs, connective tissue, cardiovascular tissue, gastrointestinal (GI) tissue, and the nervous system [6]. This is a very timely representation of the potential for viruses to induce autoimmunity and is likely to have occurred in the past in relation to post-viral syndromes and chronic inflammation.

Bystander activation can occur when virus-activated T cells kill infected cells along with uninfected neighboring cells. Cytokines and other inflammatory mediators that are released in the process increase tissue damage, which furthers the inflammatory reaction. Bystander activation occurs in the midst of an inflammatory milieu interacting with nearby tissues. This process can promote autoimmunity but may also result in a transient inflammatory event that eventually resolves [7,8]. This may explain why inflammation and autoimmunity might occur in tissues where there is no detection of the virus or other infectious agent. How and when the inflammation resolves may be dependent upon baseline inflammation and the ability of the immune system to self-regulate.

The virus may also persist at a low level where it continues to be presented on host cells leading to prolonged immunopathology. Persistent viral infections can lead to immune-mediated tissue damage due to the constant presence of the viral antigen [8]. Viral persistence may also occur when the virus has learned to evade the immune system by decreasing the host cell’s ability to present surface antigen, which alerts the immune system and results in cell destruction. Another theory regarding viral persistence is T cell exhaustion and an increase in immune system regulator cells that increase immune tolerance, resulting in failure of the immune system to purge the virus [9]. Viruses may also develop a strategy to replicate without destroying the cell in which it occupies. Persistent viruses can also occupy differentiated or specialized cells creating specific dysfunction within those cells. Examples include viruses that interfere with the ability of neurons to make neurotransmitters, block endocrine cells from making hormones, and dysregulate the production and release of immune mediators that either suppress or enhance immune function [9]. This might explain the ongoing symptoms experienced by those with ME/CFS and other complex chronic illnesses. Viral persistence seems most concerning for long COVID as it leaves the virus to linger and develop more ways to evade the host’s immune response while interfering with homeostasis and cell function.

The Gut-Lung Axis and Mucosal Immunity

Use of probiotics to support a healthy microbiome confers protection from infections through direct competition with disease-causing microbes, enhancement of epithelial barrier functions, and support of a balanced and robust immune response.

About 70% of our immune system resides in the GI tract. Our mucosal surfaces are where we encounter what is outside of ourselves. The mouth, sinuses, digestive tract, vaginal mucosa, and the lungs all directly interface with the outside world and it is through these surfaces that we encounter certain viruses. The gut microbiome directs immune function within the GI tract and beyond, and there is a bidirectional relationship between the GI tract and the lungs. The lungs also have their own microbiome that supports immune system function within the respiratory tract by modulating inflammation and creating homeostasis. The gut microbiome influences the lungs by way of the gut-lung axis and is linked through the mucosal immune system where gut bacteria-derived metabolites travel to the lungs via the mesenteric lymphatic system and general circulation. Likewise, conditions within the lungs can alter the microbiota in the GI tract [10]. Our greatest impact on mucosal immunity is through support of a healthy gut microbiome that promotes an effective immune response in the lungs via the gut-lung axis. In addition to a balanced immune response, the microbiome of various tissues supports immune tolerance so that we do not become excessively reactive to non-pathogenic antigens and regulates our response to infectious pathogens.

The diversity and volume of bacteria that makes up the microbiome may influence the severity of COVID-19, as well as the magnitude of the immune system response to the infection. Imbalances in the makeup of the microbiome may also be implicated in persisting inflammatory symptoms associated with long COVID as indicated by a recent study comparing the gut flora of patients infected with and recovering from COVID-19.  In this 100-patient cohort study, the bacterial composition of serial stool samples was compared to blood markers of inflammation. Of the 100 hospitalized patients, 27 were followed for up to 30 days past the clearance of the virus. Regardless of antimicrobial intervention, there were consistent differences in the microflora of COVID and non-COVID patients [11].

This altered concentration of bacteria was also commensurate with disease severity and researchers concluded that compositional changes play a role in exacerbating disease by contributing to dysregulation of the immune response.

Several of the bacteria that were abundant in COVID-positive patients are associated with dysregulated inflammation in other illnesses. COVID-negative patients had an abundance of bacteria that are associated with reduced inflammation and better immune system regulation. It is important to note that these alterations in microbial flora persisted beyond recovery from COVID-19. The authors went on to state that microbiome analysis may help to determine individuals at risk of severe disease and the potential development of ongoing inflammation as seen in long COVID and may also be useful in guiding intervention with specific probiotics [11]. The authors of this study also state that it has not been determined if the microbial composition of COVID-positive patients occurred prior to or as a result of the infection.

In another recently published article in Gut Pathogens, Chhibber-Goel focuses on the role of angiotensin-converting enzyme 2 (ACE2) and the ACE2 receptor that specifically applies to the infectivity of SARS-CoV-2. Chhibber-Goel states that the number of ACE2 receptors increases in the duodenum with age, which increases viral entry and replication. With increased binding of the ACE2 receptors, the production of ACE2 is reduced. In the gut, ACE2 is responsible for supporting the gut endothelium and the microbial communities within the gut by improving circulation. Impaired ACE2 expression is associated with viral infection, immune imbalance and bacterial dysbiosis in the intestines [12]. Dysbiosis of the gut modulates the immune response of neutrophils, T cell subsets, inflammatory cytokines, and TLRs, which have an influence on lung function and the ability to mount a balanced immune response [12]. As stated by Chhibber-Goel, the gut microbiome is changed during the COVID-19 infection and increases host susceptibility to other infections or potentially unmasks an underlying infection that was kept in check by a healthy microbiome and a balanced immune response. This shift in the microbiome, where there is a change in the type and volume of bacteria beyond the initial infection, has been implicated in the development of long COVID.

Use of probiotics to support a healthy microbiome confers protection from infections through direct competition with disease-causing microbes, enhancement of epithelial barrier functions, and support of a balanced and robust immune response. In addition to the gut-lung axis, the more familiar gut-brain axis is also an important consideration in the development of long COVID. Gut microbiota exerts significant effects on the central nervous system (CNS), brain neurochemistry, and activity through microbial products such as short-chain fatty acids (SCFA) and serotonin. These microbial products influence brain immunity through signaling pathways or by directly crossing the blood-brain barrier [10]. In particular, SCFAs have a role in the development and function of microglia, which are the brain’s macrophages involved in antigen presentation, phagocytosis, and modulating inflammation. The CNS also affects the gut microbiota via secretion of catecholamines that further influences gut physiology and barrier integrity via autonomic nervous system function. Modulation of gut microbiota with probiotics has shown positive effects on neuroinflammatory disorders, anxiety, depression, and symptoms associated with chronic fatigue [10]. Supporting a healthy and balanced immune response by promoting an abundant and diverse microbiome may help reduce the severity of acute COVID, as well as the lasting sequelae of long COVID.

Benefits of Reducing Viral Load Early

There are definite benefits to reducing viral replication early in the disease process. As stated earlier, what occurs in the replication phase of COVID-19 determines what will occur later in the disease—and this may also be true for long COVID. The issue is and has been that there are no broadly accepted outpatient treatments for early COVID-19 that would inhibit viral replication within the first few days of diagnosis. When considering potential pharmaceuticals to treat early COVID, the best and quickest options are repurposed medications with known safety profiles and mechanisms of action that can be effectively applied to the pathophysiology of SARS-CoV-2. Some of the options that are currently being considered fall under the categories of antivirals, immune-modulating treatments, antithrombotics, and other medications with specific actions that can prevent replication of the SARS-CoV-2 virus [13]. As early interventions are implemented, the relationship between reduced viral replication during early infection and the potential reduction in the development of long COVID will become more defined as conclusions are drawn from the data. At present, research is more focused on the immediate outcomes of reducing disease severity, hospitalization, and death.

Supporting a Healthy Immune Response

Until the world of medicine can agree upon some form of early pharmaceutical treatment that is appropriate in the outpatient setting, is scalable to large populations, and is safe, supporting the immune system and general health through nutritional supplements, dietary, and lifestyle measures are the best and most readily available options. Following a plant-rich anti-inflammatory diet that is similar in macronutrient balance to the Mediterranean diet is a good starting point and is supportive of a robust and diverse microbiome. Adding in nutritional supplements that support the immune system with targeted nutrients to slow the spread of viruses is also key. Nutrients that are helpful include vitamin D, C, A, quercetin, fish oil, zinc, selenium, NAC, probiotics, and melatonin to name a few. A good night’s sleep and regular exercise are also key in supporting the immune system and reducing stress.

Assessing Key Markers with ZRT Testing

The symptoms of long COVID include fatigue, post-exertional malaise, insomnia, cognitive difficulties, anxiety, depression, and muscle and joint pain. While an initial infection can resolve, it can leave behind an inflammatory footprint that propagates further damage. Measuring high-sensitivity C-reactive protein (hsCRP) can provide us with information regarding general inflammation. ZRT’s hsCRP can be readily measured in a dried blood spot (DBS) sample and can be combined with other ZRT cardiovascular and metabolic markers. Healthy vitamin D levels are associated with a robust and balanced immune response and can also be measured in DBS.

Some of the symptoms of long COVID are related to mood and sleep, which indicate that inflammation within the CNS can manifest as depression, anxiety, cognitive dysfunction, and sleep issues. ZRT can provide testing that may assess the potential effects of neuroinflammation in relation to neurotransmitters that impact mood, cognitive ability, and sleep.  Neurotransmitters are responsible for functionally integrating the immune and endocrine systems indicating that neurotransmitter imbalances can reach beyond the brain.

ZRT can also provide testing to assess melatonin levels, cortisol, and dihydroepiandrosterone sulfate (DHEA-S). Melatonin increases in response to darkness but may be compromised due to dysregulation within the circadian rhythm. A four-point cortisol measurement can provide an evaluation of the hypothalamic-pituitary-adrenal (HPA) axis. Elevated cortisol may indicate an elevated sympathetic tone due to common stressors, infection, pain, inflammation, and lack of sleep. DHEA-S functions in the brain and nervous system as a neurosteroid, is a potent immune-modulating hormone, and functions as a counter-regulatory hormone to cortisol. The main neurobiological effects of DHEA-S in the brain include neuroprotection, neurogenesis, apoptosis, catecholamine synthesis and secretion, antioxidant, and anti-inflammatory effects. Measuring sex hormones and thyroid markers can also provide much needed data that may help to address the symptoms associated with post-viral illness.

When addressing chronic inflammation and autoimmunity, heavy metals can have an inhibitory and excitatory effect on different branches of the immune system. Assessing and effectively removing heavy metals can help to restore a more balanced response within the immune system. ZRT Lab provides heavy metal and essential element profiles in both DBS and dried urine measuring of both toxic and essential elements.

The CDC suspects about 30% of COVID survivors may go on to develop persistent symptoms after recovery from the acute illness. While the trigger for the onset of post-viral syndromes may be a singular event, the effects are broad and involve multiple systems. As we face the burgeoning issue of long COVID, the approach to treatment will involve addressing inflammation and dysregulation within the CNS, autoimmune issues, mitochondrial function, and hormone and HPA axis dysregulation. In the next installment on long COVID, we will explore issues related to mitochondrial dysfunction and its relationship to post-viral syndrome.

ZRT Tests to Consider


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