Thread by @microbeminded2

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish Hey! Well hypoxic tissue cld lead to lower O2 extraction, & infected tissue is often hypoxic. Most intracellular pathogens hijack metabolism of cells they infect & “push” host mitochondrial metabolism to anerobic glycolysis (O2 not being used for OXPHOS): ij.hapres.com/htmls/IJ_1341_…

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish 2/ In fact many intracellular #pathogens either directly or indirectly enhance hypoxia inducible factor (HIF-1) stability. HIF-1 is a key glycolytic regulator/transcription factor whose stability reduces reliance on OXPHOS by initiating glycolytic #metabolism

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish 3/ With that in mind @VirusesImmunity, it was interesting that in your brain organoid model, you showed SARS-CoV-2 capable of infecting neurons, where it induced a locally hypoxic environment as measured by staining for HIF-1 alpha: pubmed.ncbi.nlm.nih.gov/33433624/

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish 4/ Conversely, a hypoxic environment can promote intracellular pathogen activity + survival. For example, hypoxia can induce EBV reactivation when HIF-1α binds to EBV’s primary latent-lytic switch gene: pubmed.ncbi.nlm.nih.gov/28617871/

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish 5/ It follows that 1) persistence of #SARS-CoV-2 in tissue 2) reactivation of other pathogens such as herpesviruses in #LongCovid patients might lead to a hypoxic environment in which less #oxygen is extracted from patient tissue/vasculature over time

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish 6/ Beyond that though “leakage” of organism products into blood (viral proteins, LPS etc) can activate platelets in a manner that jump-starts blood clotting cascades: pubmed.ncbi.nlm.nih.gov/12195687/

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish 7/ If that happens (either due to single pathogen activity and/or #microbiome dysbiosis) and the blood becomes more coagulated, it will have trouble perfusing the body, especially smaller capillaries

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish 8/ In some patients that could contribute to small fiber neuropathy (damage to peripheral C-fiber #nerves). That is b/c if blood perfusion via capillaries is low, the energetically demanding C-fiber nerves may die off

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish 9/ There research showing that LongCovid blood appears to be coagulated (microclots) which would support that possibility: cardiab.biomedcentral.com/articles/10.11…

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish 10/ And in conditions like sepsis, blood #clotting has been shown to lead to hypoxia/HIF activation, resulting in the release of inflammatory factors + NET formation that promotes vascular inflammation in a feed-forward fashion: ncbi.nlm.nih.gov/labs/pmc/artic…

@kimisgubbed @VirusesImmunity @KaminskiMed @Be_Kinderr @jenbrea @ahandvanish 11/ Overall I doubt that vasculature/oxygen extraction issues in #LongCovid (and #ME/CFS) patients are disconnected from the pathogens and/or microbiome dysbiosis also connected to the disease process 😉