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

[Dolphin]

Free fulltext:
https://www.mdpi.com/2673-5601/2/3/33

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

 

[Dolphin]

3.3. Long COVID/PASC Compared and Contrasted with ME/CFS

The molecular mechanism that causes sustained symptoms in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) seems to be related to the self-stimulated persistent immune cell perturbation in long COVID/PASC [8].

ME/CFS is a disease triggered by an acute viral infection but maintained by a systemic inflammatory cytokine response, chronic immune cell activation and dysregulation. There is no conclusive evidence of any long-term chronic viral infection that maintains ME/CFS, while evidence is accumulating of a chronic self-sustained immune dysfunction.

Similar to long COVID/PASC, early in disease development of ME/CFS, there is a characteristic pattern of pro-inflammatory cytokines in the plasma, in which protein concentrations of IL-1beta, IL-6, IL-8, TNFalpha and INFgamma are elevated, together with other inflammatory cytokines. However, in ME/CFS patients, in contrast to long COVID, the most upregulated gene expression is for the inflammatory cytokine IL-8, (5.6× more mRNA than healthy controls) [9].

ME/CFS patients also express 2.4× more mRNA from NFKBIA than healthy controls, which results in the production of the negative regulator NF-kB-Inhibitor-Alpha (also known as IkBa protein), a suppressor of transcription factor NFkB. In addition, ME/CFS patients also express 3.6× more mRNA from TNFAIP3, which results in the production of Tumour-Necrosis-Factor-Alpha-Induced-Protein-3 (also known as A20 protein), which inhibits further TNFa expression, in response to TNFa-induced NF-kB activation. Pro-inflammatory cascades that activate transcription factor NF-kB induce IL-1, IL-6 IL-8 and TNFa, plus a multitude of other cytokine and chemokine receptors required for immune recognition, antigen presentation, and cell adhesion.

In addition, in ME/CFS, there is also evidence of active suppression (compared to healthy controls) of expression of the cytokine-like pro-inflammatory calcium binding proteins S100A8 and S100A9, which trigger inflammatory RAGE and TLR4 signalling. In contrast, S100A8 and S100A9 expression is elevated in long COVID/PASC, and the significance of this shall be discussed later.

Similarly to long COVID/PASC patients, ME/CFS patients suffer brain-centred symptoms of neuroinflammation, including loss of homeostatic control, “brain fog” affecting cognitive ability, impaired circadian clock function, lack of refreshing sleep, and poor response to small stresses. In ME/CFS, it appears that pro-inflammatory cytokines chronically activate microglia in the brain, which further promotes inflammation and neurological dysfunction.

Neuroinflammation activates microglia to release Reactive Oxygen Species (ROS) that have a destructive effect on mitochondria. Neuroinflammation is closely associated with mitochondrial dysfunction, compromised energy production and further oxidative stress. Immortalized lymphocytes from ME/CFS patients have dysregulated mitochondrial function and inefficient production of ATP by Complex-V of the mitochondrial electron transport chain. The interdependence of oxidative stress, neuroinflammation and mitochondrial dysfunction are causative of many of the common symptoms seen in ME/CFS and long COVID/PASC.

In addition, both CD4+ T-cells and CD8+ T-cells from ME/CFS patients have reduced glycolysis at rest and CD8+ T-cells also have reduced glycolysis following activation. However, resting glycolysis in long COVID is higher than healthy controls, in contrast to ME/CFS.

 

[Jaybee00]

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.

 

[Jaybee00]

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

 

[Jonathan Edwards]

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.

 

[Peter T]

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.