Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement.
The messenger RNA (mRNA) vaccines for COVID-19, Pfizer-BioNTech and Moderna, were authorized in the US on an emergency basis in December of 2020. The rapid distribution of these therapeutics around the country and the world led to millions of people being vaccinated in a short time span, an action that decreased hospitalization and death but also heightened the concerns about adverse effects and drug-vaccine interactions. The COVID-19 mRNA vaccines are of particular interest as they form the vanguard of a range of other mRNA therapeutics that are currently in the development pipeline, focusing both on infectious diseases as well as oncological applications. The Vaccine Adverse Event Reporting System (VAERS) has gained additional attention during the COVID-19 pandemic, specifically regarding the rollout of mRNA therapeutics. However, for VAERS, absence of a reporting platform for drug-vaccine interactions left these events poorly defined. For example, chemotherapy, anticonvulsants, and antimalarials were documented to interfere with the mRNA vaccines, but much less is known about the other drugs that could interact with these therapeutics, causing adverse events or decreased efficacy. In addition, SARS-CoV-2 exploitation of host cytochrome P450 enzymes, reported in COVID-19 critical illness, highlights viral interference with drug metabolism. For example, patients with severe psychiatric illness (SPI) in treatment with clozapine often displayed elevated drug levels, emphasizing drug-vaccine interaction.
Gut microbes are immunologically tolerated in the gastrointestinal tract but trigger aggressive immune responses upon translocation across the gut barrier. Although oral tolerance, a physiological process that dampens immune responses to food proteins and commensal microbiota, remains poorly defined, significant progress was made during and after the Human Immunodeficiency Virus epidemic in the 1980s and the discovery of regulatory T cells in 1995. Additional insight was gained after the discoveries of innate lymphoid cells in 2008 and the functional elucidation of mucosal mast cells. Prior to the historical discovery of human pathogens, the etiologies of most human diseases were considered unknown. The same was true about many genetic disorders prior to the Human Genome Project. Here, we hypothesize that many of the remaining idiopathic conditions, including autoimmune, fibroproliferative, and neuropsychiatric diseases as well as some cancers, can be considered microbial translocation disorders triggered by the host immune responses to extraintestinal gut microbes and/or their constituent parts. In addition to microbial translocation, we also discuss potential interventions for intestinal barrier rehabilitation, including antibodies against tumor necrosis factor-like ligand 1A and membrane lipid replacement supplements.
We read with great interest the paper by Beaudoin CA et al. "Are There Hidden Genes in DNA/RNA Vaccines?", reporting overlapping sequences between the SARS-CoV-2 spike (S) glycoprotein and two viral genes [1]. If translated, the undesired proteins may cause rare, untoward effects, including those recorded in Vaccine Adverse Event Reporting System (VAERS).These findings are in line with our own research and that of others however, aside from overlapping genes (OLGs), the S protein also contains overlapping molecular structures and signals (heptad repeats, simple sequence repeats, calcium calmodulin kinase II, and prion-like domains) that can lead to VAERS-recorded pathology [2-6].
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