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In a nutshell, this study illustrates that respiratory-only mild SARS-CoV-2 infection can lead to detrimental changes in the brain, likely mediated by inflammatory factors. Similar neuropathobiology may be shared in chemo-brain, post-ICU syndrome and ME/CFS. (15/)
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This study was led and executed by my amazing colleague, @michelle_monje & her team + @PutrinoLab @MountSinaiNYC, @nathavindra et al. From our Yale team, I wish to highlight @peowenlu @ericsongg and others listed here 💪🏼 (14/)
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This loss of oligodendrocytes was accompanied by reduced myelinated axon density in subcortical white matter within 7 days of infection. This could lead to ⬇️ neural circuit function, axon health and to numerous deleterious neurological consequences of SARS-CoV-2 infection. (13/)
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What other changes are happening in the brain of mice with mild respiratory infection? Within just 7 days of infection, we found a loss of ~1/3 of oligodendrocytes, which persisted for at least 7 weeks! Analysis by @ThisIsAnthonyFC and @AnnaGeraghty2 (12/)
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In collaboration with @PutrinoLab at @MountSinaiNYC, we found significantly elevated circulating levels of CCL11 in long COVID patients who reported brain fog vs. those who did not. Many 🙏🏼 to @wood_jamie_1 @LauraTabacof @GeneticHeartDoc #DaynaMcCarthy & the patients! (11/)
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What can lead to impaired neurogenesis in hippocampus? We looked into a chemokine called CCL11 (eotaxin-1) which was shown to reduce neurogenesis (Villeda et al). In our mice, CCL11 was elevated in the CSF 7 weeks after mild respiratory infection. (10/)
pubmed.ncbi.nlm.nih.gov/21886162/
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Neurogenesis in the hippocampus is thought to support memory function. Reactive microglia can impair this process. Indeed, mice that had mild SARS-CoV-2 infection 7 days or 7 weeks prior had significantly lower # of neuroblasts than controls. This could ⬇️ memory function. (9/)
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Next, with @nathavindra, autopsies from 9 individuals found to be SARS-CoV-2-positive by nasal swab PCR at the time of death were examined. Brains from those with even mild or asymptomatic SARS-CoV-2 infection had microglial reactivity in subcortical white matter. (8/)
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What does a respiratory-only mild COVID do to the brain? @ThisIsAnthonyFC and @AnnaGeraghty2 examined the subcortical white matter of two independent strains of mice and found consistently increased microglial reactivity at 7 days and 7 weeks post infection. (7/)
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Somewhat unexpectedly, we also see that some of these cytokines remain elevated at 7 weeks post infection in both sera and CSF. Similarly elevated cytokines have been reported from the sera of long COVID patients by others, months after primary infection. (6/)
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So what do systemic (serum) and local (cerebrospinal fluid; CSF) cytokines look like after this mild respiratory-only infection? Not surprisingly, we see many elevated cytokines 7 days after infection in the serum. We also see elevated cytokines in the CSF. (5/)
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In fact, mice infected only in the respiratory tract show no evidence for weight loss (a disease measurement)(B),and no evidence of SARS-CoV-2 infection in the brain (C). (4/)
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To achieve this goal, @peowenlu & @ericsongg used a mouse model developed by @BenIsraelow & @ericsongg in which we can control where the infection happens. Using AAV-hACE2 intratracheally, we can confine the SARS-CoV-2 infection only to the lungs. (3/)
rupress.org/jem/article/21…
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How can a mild respiratory SARS-CoV-2 infection lead to longterm neurological symptoms? Possibilities include 1) direct infection of 🧠, 2) autoimmunity, and 3) inflammatory impact of infection distal to the 🧠. In this study, we focused on 3) 👇🏽 (2/)
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So excited to be a part of this important study led by @michelle_monje on how significant longterm neurologic damage can occur after a mild respiratory-only SARS-CoV-2 infection. My own🧵on the findings of this study with relevance to #longCovid (1/)
biorxiv.org/content/10.110…
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Has anyone else with #longCOVID received monoclonal antibodies to SARS-CoV-2? Please share your experience. More data will help justify a clinical trial. Thank you. twitter.com/AlisaValdesRod…
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In terms of public health, CoronaVac 2x is insufficient to neutralize Omicron. Even with CoronaVac 2x plus Pfizer booster, NAb is only 1.4x higher than 2x mRNA alone. Thus, CoronaVac recipients may need 2 additional booster doses to reach levels needed against Omicron. (10/)
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Unfortunately, in the CoronaVac 2x recipients boosted with Pfizer mRNA vax, prior infection made no difference to the neutralization capacity against Omicron. (8/)
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In CoronaVac fully vaccinated (2x) people, there was NO detectable neutralization against the infectious Omicron virus. Antibodies were assayed at mean days from second Coronavac shot of 113 days (with SD 33 days). (5/)
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CoronaVac is an inactivated SARS-CoV-2 vaccine approved for use in 48 countries. In collaboration with the Ministry of Health in Dominican Republic, we tested whether CoronaVac (2x) + Pfizer booster induces neutralizing Abs to Delta and Omicron. (1/)
medrxiv.org/content/10.110…
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In #longCOVID patients, “exercise capacity was primarily limited by impaired systemic EO2 of such severity that what should have been an adequate increase in DO2 was insufficient to allow for an increase in VO2.” Via @YalePCCSM
sciencedirect.com/science/articl…
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So the problem in #longCOVID is not necessarily O2 supply (thus normal cardiopulmonary function) but O2 extraction and thus consumption by tissue. What could cause such defects? Microvascular abnormality? I would love expert input here. @KaminskiMed, @CharleszYaleMed?
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This thread is about our new preprint on transposable element called long interspersed nuclear elements (LINE-1/L1). When expressed excessively in the cerebellum, L1 causes ataxia (impaired coordination).
A fascinating finding by @taka_takehiro 👇🏽 (1/)
biorxiv.org/content/10.110…
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These results indicate that nasal vaccines induce IgA and promote better cross-protective immunity against viral variants, and suggest its utility in combating COVID-19 variants of concern. A great write up by Bill Hathaway. (13/)
news.yale.edu/2021/12/10/nas…
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Our new study by @JieunOh9 @ericsongg @MiyuMoriyama et al shows that immune priming via intranasal route provides superior protection against heterologous respiratory virus challenge. The key is in inducing local secretory IgA with broader coverage. (1/)
science.org/doi/10.1126/sc…
We study innate and adaptive immunity against viruses and study disease pathogenesis. #COVID19 #longCOVID #vaccines @HHMINEWS @YaleIBIO @YaleMed @YaleCII