In a meeting I watched today, microglia priming was mentioned in #LongCovid and #ME/CFS. It’s important to clarify what “microglia priming” means. Microglial priming does not mean that after a trigger has “cleared” microglia remain perpetually activated
2/ Instead, microglia priming goes like this 👉 When microglia or other glial cells detect #infection, injury, or inflammatory mediators, they enter a state of activation in which they change morphology and release their own neuroexcitatory inflammatory mediators
3/ Then, after activating, they retain a “primed” functional state which causes an even more robust response to *subsequent* infectious/immune/#inflammatory challenges. And as cells, microglia live long lives (they are not replaced as often as many other cell types)
4/ So microglia can remain in a “primed” state over long periods of time, but there needs to be subsequent infectious or inflammatory events that drive primed microglial cells into a hyperactivated state
5/ If a person doesn’t fully clear an infection (#SARS-CoV-2 or other neurotrophic pathogens) from the brain itself, that will sustain microglia activation. Brainstem compression (aka CCI) can also act as an #injury-based stimulus of microglial activation
6/ However microglial activation can also be sustained by other inflammatory/infectious events outside the #brain. That’s b/c the vagus #nerve (which connects to the brainstem) extends into most organs of the body
7/ If the vagus nerve senses #inflammation (especially cytokine activation) in these other body sites, it signals to the brainstem in a manner that generates a “mirror response” of microglia activation in the brainstem itself
8/ Inflammatory event in the periphery of the body that can be sensed by the vagus nerve to cause this microglia “mirror” response in the brainstem include acute/ongoing infections, #microbiome dysbiosis, injury etc.
9/ Again it is the collective nature of these different microglia-activating events that leads to a primed state. The first “hit” makes the activated microglia respond more dramatically to the second, causing more profound #neuroinflammation
10/ That’s why it’s no suprise that many #ME/CFS and even #LongCovid patients report multiple “hits” in their cases. A #brain injury and an infection. Or gut micorbiome dysbiosis and mold exposure. Each of these might converge to drive microglial priming
11/ To better understand what I’m saying, watch @MBVanElzakker’s recent talk at the @polybioRF Seminar Series where he explains how infectious/immune/gut microbiome/vagus nerve signaling can converge on microglia activity/priming in the dorsal brainstem:
12/ This matters for #treatment in LongCovid or ME/CFS. We can shut down microglial signaling with inhibitory drugs. But if we also clarify the infectious/inflammatory/injury-related events that prime microglia in the first place, and treat those issues too, patients cld benefit
13/ Also, b/c many different kinds of infectious, inflammatory, or injury-based insults can activate vagus nerve/brainstem/microglia signaling, not every #patient has to have the exact same insults to develop similar symptoms, which opens the door to personalized #medicine
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Thanks @DrDavidACox for interviewing me for this article on #LongCovid. There’s also great info in the article on research showing #viral RNA in the brains of patients w/ post-SARS syndrome, and viral reservoirs in patients w/ post-Ebola Syndrome: bbc.com/future/article…
2/ The article reads: “Amy Proal, a microbiologist who runs the @polybioRF which studies the causes of chronic inflammatory diseases, believes that small amounts of #pathogens that linger beyond the reach of the immune system in remote pockets of the body...
3/ “...known as reservoirs or anatomical sanctuaries, are at least partially responsible for a whole range of post-infectious syndromes. This includes long #Covid, but also a number of mysterious illnesses which have puzzled scientists for decades, such as chronic Lyme disease..
Preprint reports elevated serum inflammatory cytokine profile in #LongCovid subjects. Worth noting that an ongoing immune response towards persistent viral reservoirs of #SARS-CoV-2 and/or antigen could explain the findings: medrxiv.org/content/10.110…
2/ So the findings underscore the need to do studies that obtain tissue (via surgery or biopsy if possible) to search for #SARS-CoV-2/antigen in #LongCovid patients. Similar to what this team did (and found viral RNA/antigen in multiple tissue types!): gut.bmj.com/content/early/…
3/ Studying both the LongCovid immune response AND possible #viral reservoirs is very important for LongCovid patients to get the best treatment. If you assume the #immune response alone is the problem, standard of care could become immunosuppressive drugs
If you’re considering studying blockage of GPCRs in #LongCovid or related conditions, please start w/ the understanding that humans are not sterile...and that common human organisms/pathogens express proteins/metabolites that block/dysregulate GPCR signaling
2/ Herpesvirus re-activation is common in #COVID-19, and may impact some LongCovid cases. The herpesviruses alone (EBV, CMV etc) create a wide range of proteins that block GPCR signaling: ncbi.nlm.nih.gov/pmc/articles/P… Indeed, viral hijacking of GPCRs is a big topic in cancer research
3/ Beyond that, many commensal #bacteria derived from the human #microbiome appear capable of expressing metabolites that are GPCR mimics, that directly impact GPCR signaling. That means even changing microbiome dynamics could impact GPCR-related issues: ncbi.nlm.nih.gov/pmc/articles/P…
Happy 2021! @MBVanElzakker and I are excited to share our new article published in #Immunometabolism: “Pathogens Hijack Host Cell Metabolism: Intracellular Infection as a Driver of the Warburg Effect in Cancer and Other Chronic Inflammatory Conditions”: ij.hapres.com/htmls/IJ_1341_…
2/ In the paper, we detail molecular mechanisms by which #viral, #bacterial, and #parasite intracellular pathogens can induce, or contribute to, a Warburg-like #metabolism in infected host cells in order to meet their own replication and nutritional needs.
3/ We also discuss how host defense towards #infection may impact cellular metabolic changes (including how #mitochondria can participate in the innate immune response towards infection)
It was inspiring to virtually attend the first Inaugural Robert D. Moir Symposium this past Friday. Rob was a friend and constant source of inspiration, plus an amazing sounding board for novel ideas. He passed away from glioblastoma one year ago today.
2/ Like most great scientists I’ve known, Rob was not content to study just the presence or absence of compounds/organisms in the human body. Instead his thinking continually gravitated towards the vital question of “what are they DOING??”
3/ Via that lens - the constant question of “why?” and a passion for characterizing the molecular biology of the “why?”...Rob uncovered that amyloid in the #Alzhiemer’s brain has a function (it appears to act as an antimicrobial peptide)
1/ This excellent study by @aaronmring/@VirusesImmunity and team found that COVID-19 patients exhibit dramatic increases in the production of antibodies against thousands of human extracellular and secreted proteins (the exoproteome) compared to controls 👇
2/ The million dollar question is: what molecular mechanisms underly this antibody/#autoantibody production? It is worth interpreting the findings via the lens of human #microbiome/#virome activity + the activity of persistent pathogens (such as EBV) harbored by study subjects.
3/ Every study subject harbored extensive microbiome/virome communities comprised of trillions of organisms during #COVID-19 infection…with such ecosystems now understood to persist beyond just the gut but also in other body sites (#lung, liver etc).