Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9>TLR4/RAGE Signalling,2022,Holms - has ME/CFS section

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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
by
Rupert Donald Holms


Newal R&D Ltd., London NW1 7SX, UK
Academic Editor: Stefano Aquaro
Immuno 2022, 2(3), 512-533; https://doi.org/10.3390/immuno2030033
Received: 1 August 2022 / Revised: 31 August 2022 / Accepted: 5 September 2022 / Published: 8 September 2022


Abstract: 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 SARS-CoV-2 Spike-protein binding and hyper-activating the cell-membrane expressed Receptor for Advance Glycation End-products (mRAGE) and Toll-Like Receptor 4 (TLR4). SARS-CoV-2 infects lung monocytes by Spike binding to mRAGE (not ACE2). During acute COVID-19, high levels of IL-6 hyper-stimulate S100A8/A9 expression and secretion. Although no viral protein nor mRNA can be detected in half of long COVID (PASC) patients, there is a significant elevation of serum levels of IL-1b, IL-6, TNFa, and S100A8/A9. It appears that a pathological pro-inflammatory feedback loop (the TLR4/RAGE-loop) is established during acute COVID-19, which is maintained by S100A8/A9 > RAGE/TLR4 chronic inflammatory signalling, even after SARS-CoV-2 has been cleared from the body. During long COVID/PASC, Ca2+-binding protein S100A8/A9 chronically stimulates TLR4/RAGE-signalling to induce chronic expression of IL-1b, IL-6 and TNFa. Secreted IL-6 binds to its IL-6R receptor on the surface of other cells and signals via STAT3 and C/EBPb for more S100A8/A9 expression. Secreted IL-1b binds to its receptor IL-1R on other cells, and signals via NFkB for more mRAGE and TLR4 expression. New S100A8/A9 can bind and activate cell-surface mRAGE and TLR4 to stimulate expression of more IL- 1b, IL-6 and TNFa. This process establishes a pathogenic pro-inflammatory TLR4/RAGE-loop: IL-1b + IL-6 > IL-1R + IL-6R > TLR4/mRAGE + S100A8/A9 > IL-1b + IL-6, which generates multi-organ inflammation that persists in the blood vessels, the brain, the liver, the heart, the kidneys, the gut and the musculo-skeletal system, and is responsible for all the complex pathologies associated with long COVID/PASC. Chronic expression of IL-1, IL-6 and TNFa is critical for the maintenance of the TLR4/RAGE-loop and persistence of long COVID/PASC. Ezrin peptides are inhibitors of IL-1, IL-6, IL-8 and TNFa expression, so are now being investigated as potential therapy for long COVID/PASC. There is preliminary anecdotal evidence of symptomatic relief (not confirmed yet by formal clinical trials) from a few long COVID/PASC patient volunteers, after treatment with ezrin peptide therapy. Keywords: long COVID; PASC; RAGE; TLR4; p38MAPK; IL-1b; IL-6; IL-8; TNFa; S100; S100A8/A9; AGE; HMGB1; ezrin peptide therapy; HEP-1; RepG3


Keywords: long COVID; PASC; RAGE; TLR4; p38MAPK; IL-1b; IL-6; IL-8; TNFa; S100; S100A8/A9; AGE; HMGB1; ezrin peptide therapy; HEP-1; RepG3

 

Conflicts of Interest: Rupert D Holms is inventor of ezrin peptide technology and issued patents in various territories are owned by NewalR&D Ltd, London, a company owned by Rupert D Holms.

 

FWIW Ezrin peptides have been trialed by some MECFS patients without much success.

 

This is just wrong. Forget it. God knows how the publication system has come to the point where this is considered publishable.

There is no ongoing multi-organ inflammation in Long Covid. That is why it is mysterious. If there is persistent signalling involving something like TLR-4 then it is doing something else.

 

Please can teachers of scientific research methodology get across to their students the difference between ‘it may be’ or ‘it is a possibility’ and ‘it is definitely the case that’.

I bought a lottery ticket and so may win the top prize at no level carries the necessity that I will win the jackpot.