What a coincidence
“The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in other SARS-related coronaviruses), which is highly similar in both sequence and structure to the bacterial superantigen staphylococcal enterotoxin B”
pnas.org/content/117/41…
Now, this story keeps unfolding.
“the trimeric spike protein of SARS-CoV-2 could bind to TLR4 directly and robustly activate downstream signaling in monocytes and neutrophils.” Via MyD88 and NFκB
See how MyD88 activation is THE problematic pathway, especially when amplified by elevated LPS exposure. I.e. by metabolic diseases.
How the two pathways join at this signaling node
👇🏻👇🏻👇🏻
journals.sagepub.com/doi/10.1177/17…
“the most profound disturbances including a prominent neutrophil hyperactivation signature and monocytes with anti-inflammatory features. We further demonstrate that emergency myelopoiesis is a prominent feature of fatal COVID-19.”
Monocytes featuring trained innate immunity?
Evidence that this may in fact work the same way in practice!
I can hardly wait for in vivo confirmation.
“an anti-SEB monoclonal antibody (mAb), 6D3, can bind this viral motif, and in particular its PRRA insert, to inhibit infection by blocking the access of host cell proteases, TMPRSS2 or furin, to the cleavage site.”
I was about to abandon this thread until in vivo evidence emerges, extending the separate thread on TLR4, but then I found this… There’s convergence/amplification. And of course the visceral fat connection (LPS ⇨ TLR4).
pubmed.ncbi.nlm.nih.gov/15504761/
Deletion of the “newly acquired” furin cleavage site, which appears to be part of a SEB motif as well, results in attenuated disease, but the mutant still confers protection against wild SARS-CoV-2 infection.
Somebody should find the TLR4 binding site, too
nature.com/articles/s4158…
The spike protein has characteristics that keep amazing me. This study shows that it binds and aggregates bacterial lipopolysaccharide, exacerbating (innate, TLR4) inflammatory signaling.
academic.oup.com/jmcb/advance-a…
Welcome to the land of MyD88 signaling & extreme peptide mimicry.
"cytokines that activate the NF-kB pathway can induce Activin A and its downstream marker, FLRG. Patients with Activin A/FLRG above the sample median were 2.6/2.9 times more likely to die" biorxiv.org/content/10.110…
Periodontal disease could make one prone to severe COVID-19/death via the same overstimulated pathways.
Recent findings (H/T @mbiranek) efp.org/news-events/ne…
Pathway studies onlinelibrary.wiley.com/doi/10.1111/od…
ejh.it/index.php/ejh/…
Not only TLR4: “N protein activates endothelial cells via TLR2-mediated NF-κB and MAPK signal pathways.” Again, other CoV NPs do not activate this pathway… another novel feature.
Note that abamectin❗️also blocked this action.
biorxiv.org/content/10.110…
“S protein triggers inflammation via activation of the NF-κB pathway in a MyD88-dependent manner. Further, such an activation of the NF-κB pathway is abrogated in Tlr2-deficient macrophages. …administration of S protein induces IL-6, TNF-α, and IL-1β” biorxiv.org/content/10.110…
“SARS-CoV-2 spike proteins bind heparan sulfate and activate the alternative complement pathway on cell surfaces.”
“the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC).”
ashpublications.org/blood/article/…
In case anybody lacks understanding about the link to metabolic diseases, let’s tie up the thread from the other end:
“In this review, we present evidence for a pivotal role of TLR-induced inflammation in both obesity and MetS”
academic.oup.com/jcem/article/9…
“Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCR Beta Variable gene (TRBV)11-2. Furthermore, TRBV11-2 skewing was remarkably correlated with MIS-C severity and serum cytokine levels.”
H/t @BillyBostickson
biorxiv.org/content/10.110…
Peculiar features of the virus keep emerging.
“factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing viral entry.
We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity. biorxiv.org/content/10.110…
🧐 “a striking difference was observed in the distribution of prion-like domains in the spike protein, since SARS-CoV-2 was the only coronavirus with a prion-like domain found in the receptor-binding domain of the S1 region of the spike protein.” preprints.org/manuscript/202…
Note the signaling pathways implicated in inflammaging and how the virus (mostly the spike glycoprotein) overstimulates precisely the same inflammatory processes. The collision of aging societies, widespread metabolic diseases, and fine tuned viral fragments.
Supporting evidence in a human cohort.
COVID-19 Patients Upregulate Toll-like Receptor 4-mediated Inflammatory Signaling That Mimics Bacterial Sepsis doi.org/10.3346/jkms.2…
“we identified several C-type lectins and Tweety family member 2 as glycan-dependent binding partners of the SARS-CoV-2 spike. …their engagement with virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity.”
cell.com/immunity/fullt…
The envelope protein binds TLR2, and its blockade results in attenuation of disease.
SARS-CoV-2 binds to human epithelial cells and causes permeability.
SARS-CoV-2 uses major endothelial integrin αvβ3 to cause vascular dysregulation in-vitro during COVID-19
journals.plos.org/plosone/articl…
“the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and enhanced the expression of leukocyte adhesion molecules VCAM1 and ICAM1, the adhesion of peripheral blood leukocytes, and the permeability of the monolayer.”
biorxiv.org/content/10.110…
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