billwilliam

Metalloproteinases (MMP) are activated by inflammatory cytokines, Reactive oxygen species (ROS), and angiotensin II. [1] The spike protein’s interactions with TLR2/4 and integrin probably drive inflammation. The spike protein also competitively inhibits ACE2 function, and the resultant buildup of angiotensin II leads to inflammation and production of ROS. Excess MMP activity drives carcinogenesis. By the same token, these stimuli also drive cancer angiogenesis. Cytokine storm, VEGF (from hypoxia and HIF activation), endothelial cell (EC) dysfunction, dysregulated Renin-angiotensin-aldosterone system (RAAS), and thrombosis contribute to angiogenesis. [2] Spike protein promotes production of inflammatory cytokines (for example IL-6) by interaction with Toll-like receptors. Hypoxia-Inducible Factor (HIF-1) can be activated by either hypoxia or hypoxia-independent mechanism. Phosphatidylinositol 3-kinase (PI3K), which is downstream of TLR activation, also enhances HIF translation and subsequent VEGF production in hypoxia-independent mechanism. [3] “Hormones such as angiotensin II and platelet-derived growth factor stimulate the HIF pathway by increasing HIF-1α protein levels via production of reactive oxygen species (ROS) within the cell.” [3] Excess angiotensin II also stimulates HIF pathway and VEGF production. References: 1. Salomão R, Assis V, de Sousa Neto IV, Petriz B, Babault N, Durigan JLQ, de Cássia Marqueti R. Involvement of Matrix Metalloproteinases in COVID-19: Molecular Targets, Mechanisms, and Insights for Therapeutic Interventions. Biology (Basel). 2023 Jun 10;12(6):843. doi: 10.3390/biology12060843. PMID: 37372128; PMCID: PMC10295079. pubmed.ncbi.nlm.nih.gov/3737… 2. Madureira G, Soares R. The misunderstood link between SARS-CoV-2 and angiogenesis. A narrative review. Pulmonology. 2023 Jul-Aug;29(4):323-331. doi: 10.1016/j.pulmoe.2021.08.004. Epub 2021 Aug 27. PMID: 34593362; PMCID: PMC8390375. pubmed.ncbi.nlm.nih.gov/3459… 3. Ziello JE, Jovin IS, Huang Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007 Jun;80(2):51-60. PMID: 18160990; PMCID: PMC2140184. pubmed.ncbi.nlm.nih.gov/1816…

That’s a possibility. A virus triggers auto-antibodies by three mechanisms: 1) Anti-idiotype network 2) molecular mimicry (similar motifs) 3) tissue damage and release of self antigen Autoantibodies against GPCR may be raised by anti-idiotype mechanism. The word “idiotype” refers to the antigen-binding part of an antibody. The viral spike protein elicits primary antibodies (Ab1), and if the level of Ab1 is too high, the body also produces secondary antibodies (Ab2) attacking the primary antibodies at the idiotype site. Ab1 is complementary to epitope on the spike protein, while Ab1 is also complementary to Ab2. Therefore, Ab2 may mimic the spike protein in shape, and Ab2 may behave like the spike protein to interact with human receptors. “Collins et al. [108] showed that sequential SARS-CoV-2 mRNA vaccination of hACE2 transgenic mice can induce both anti-S and anti-ACE2 antibody responses, and the latter was gradually amplified with each boost.” The spike protein raises antibodies against both the spike protein and the ACE2 receptor. Given that SARS-CoV-2 spike RBD binds β-adrenergic receptors with high affinity, the spike protein probably elicits autoantibodies against β-adrenergic receptors by anti-idiotype mechanism. In addition, some of the spike motifs mimic human proteins in the blood coagulation pathway, thus inducing production of pro-thrombotic autoantibodies. For example, TQLPP motif on spike mimics thrombopoietin and may induce thrombocytopenia. ELDKY motif on spike mimics protein kinase G1 (involved in platelet activation). Spike RBD may share some degree of similarity with angiotensin II, since both function as ligands for ACE2 receptor. Antibody targeting spike RBD may cross-interact with angiotensin II, leading to undesired vascular pathology such as hypertension. Some parts of spike protein mimic ACE2. “Segments of the SARS-CoV-2 S protein (residues 49–53, 226–230, 418–428, 529–536, 744–774, and 977–980) share structural and chemical similarities with some segments of the ACE2 receptor (residues 137–141, 335–345, 350–352, 463–471, and 545–573).” ACE2 converts angiotensin II (DRVYIHPF) into angiotensin (1-7) (DRVYIHP). A G-protein-coupled receptor MAS1 binds angiotensin (1-7) to mediate vasodilation. Because the two receptors use very similar ligands, the ligand-binding sites on these receptors are also similar. Anti-ACE2 antibody may cross-react with MAS1. Reference: Bellavite P, Di Fede G, Mantovani M, Zanolin E. Autoimmune Features of Post-COVID-19 Vaccination Syndrome and Their Impacts on the Renin-Angiotensin System. Vaccines (Basel). 2026 Apr 16;14(4):354. doi: 10.3390/vaccines14040354. PMID: 42042830; PMCID: PMC13120093. pubmed.ncbi.nlm.nih.gov/4204…

@tommy_cleary @ProGof39474 I found a few Chinese gain-of-function papers on Yersinia pestis. General Ruifu Yang and colleagues engineered ultra virulent versions of bubonic plague, which killed lab mice at faster rate than wildtype germs. I think they attempt to weaponize plague. Bubonic plague switches between two forms during its life cycle: A) biofilm-forming, less-virulent form and B) non-biofilm-forming, virulent form. The plague germ adopts biofilm-forming, less-virulent form in low ambient temperature (21 degrees Celsius) such as flea digestive tract. The biofilm blocks the flea’s gut and induces the flea to bite more frequently, increasing disease transmission. A master regulator gene RovM promotes biofilm formation and represses RovA. Virulence factors are downregulated so that the germ doesn’t kill the flea immediately. The plague germs adopt highly virulent form under high ambient temperature (37 degrees Celsius) such as inside body of warm-blooded animal. RovM is repressed under high temperature. RovA becomes activated and promotes production of virulence factors. I don’t want to explain too explicitly. You are welcome to read these papers. Basically, Gen. Yang tweaked with bacterial signaling pathway to create super lethal mutant plague germs that produce virulence factors consistently. References: 1. Chen H, Cao S, Zhou Y, Wang T, Jiao Y, Tan Y, Wu Y, Ren Y, Song Y, Zhang JR, Du Z, Yang R. Molecular turn in Yersinia pestis pathogenesis: implications of the gppAframeshift for bacterial survival in human macrophage. Emerg Microbes Infect. 2025 Dec;14(1):2467778. doi: 10.1080/22221751.2025.2467778. Epub 2025 Mar 3. PMID: 39945756; PMCID: PMC11878169. pubmed.ncbi.nlm.nih.gov/3994… 2. Liu L, Fang H, Yang H, Zhang Y, Han Y, Zhou D, Yang R. Reciprocal regulation of Yersinia pestis biofilm formation and virulence by RovM and RovA. Open Biol. 2016 Mar;6(3):150198. doi: 10.1098/rsob.150198. PMID: 26984293; PMCID: PMC4821237. pubmed.ncbi.nlm.nih.gov/2698… 3. Liu Z, Gao X, Wang H, Fang H, Yan Y, Liu L, Chen R, Zhou D, Yang R, Han Y. Plasmid pPCP1-derived sRNA HmsA promotes biofilm formation of Yersinia pestis. BMC Microbiol. 2016 Aug 4;16(1):176. doi: 10.1186/s12866-016-0793-5. PMID: 27492011; PMCID: PMC4973556. pubmed.ncbi.nlm.nih.gov/2749… 4. Gao X, Wang M, Liu Z, Bi Y, Song Y, Yang R, Han Y. Altered Yersinia pestisvirulence is associated with the small regulatory RNA HmsA encoded on the plasmid pPCP1. Future Microbiol. 2020 Sep;15:1207-1215. doi: 10.2217/fmb-2019-0319. PMID: 33026884. pubmed.ncbi.nlm.nih.gov/3302… Also read the paper below. A CCP scientist and US scientists collaborated on Yersinia research (just comparative genetics, not GOF). “This research was supported by the Intramural Research Program of the NIH, NIAID.” Chouikha I, Sturdevant DE, Jarrett C, Sun YC, Hinnebusch BJ. Differential Gene Expression Patterns of Yersinia pestis and Yersinia pseudotuberculosis during Infection and Biofilm Formation in the Flea Digestive Tract. mSystems. 2019 Feb 19;4(1):e00217-18. doi: 10.1128/mSystems.00217-18. PMID: 30801031; PMCID: PMC6381227. pubmed.ncbi.nlm.nih.gov/3080…