Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9 > TLR4/RAGE Signalling, Inducing Chronic Expression of IL-1b, IL-6 and TNFa: Anti-Inflammatory Ezrin Peptides as Potential Therapy

Long COVID, also referred to as Post-Acute Sequelae of COVID (PASC), is probably triggered during SARS-CoV-2 infection and acute COVID-19 by Spike-protein binding hyper-activating the cell-membrane expressed Receptor for Advance Glycation End-products (mRAGE) Toll-Like 4 (TLR4). infects lung monocytes Spike mRAGE (not ACE2). During COVID-19, high levels IL-6 hyper-stimulate S100A8/A9 expression secretion. Although no viral protein nor mRNA can be detected in half long (PASC) patients, there a significant elevation serum IL-1b, IL-6, TNFa, S100A8/A9. It appears that pathological pro-inflammatory feedback loop (the TLR4/RAGE-loop) established which maintained > RAGE/TLR4 chronic inflammatory signalling, even after has been cleared from body. COVID/PASC, Ca2+-binding chronically stimulates TLR4/RAGE-signalling induce TNFa. Secreted binds its IL-6R receptor on surface other cells signals via STAT3 C/EBPb more expression. IL-1b IL-1R cells, NFkB TLR4 New bind activate cell-surface stimulate This process establishes pathogenic TLR4/RAGE-loop: + TLR4/mRAGE generates multi-organ inflammation persists blood vessels, brain, liver, heart, kidneys, gut musculo-skeletal system, responsible all complex pathologies associated with COVID/PASC. Chronic IL-1, TNFa critical maintenance TLR4/RAGE-loop persistence Ezrin peptides are inhibitors IL-8 expression, so now being investigated potential therapy There preliminary anecdotal evidence symptomatic relief confirmed yet formal clinical trials) few COVID/PASC patient volunteers, treatment ezrin peptide therapy.