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/)
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/)
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/)
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/)
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/)
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/)
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/)
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/)
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/)
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/)
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/)
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/)
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/)
This study also opens up all kinds of questions and possibilities. For example, therapies that can 1) block inflammatory cytokines, 2) block inducers of such cytokines, or 3) reset reactive microglia can be considered for future clinical trials. Thank you for reading till end.
I highly recommend this very informative thread posted by @michelle_monje on this study.
Sharing our new study by @keylas3, @SilvaJ_C, Rafael Bayarri Olmos et al (with T. Horvath & @PutrinoLab) showing that a passive transfer of IgG from patients with #longCOVID into mice recapitulates ⬆️ pain and other symptoms 🧵 (1/)
Long COVID disease pathogenesis includes persistent SARS-CoV-2 virus, dysbiosis, herpesvirus reactivation, autoimmunity, and others. In this study, we focus on the role of autoantibodies. (2/)
Among the original Mount Sinai-Yale Long COVID study participants 👇🏼 (with @PutrinoLab), we focused on patients with high neurological symptom burden (n=55), and compared antibodies with convalescent controls (n=42) or uninfected controls (n=39). (3/) nature.com/articles/s4158…
What determines whether someone gets infected or not after exposure to SARS-CoV-2? A new study by Lindeboom et al examined this question with COVID-19 human challenge study. @BenIsraelow and I summarize their key findings in this News & Views 🧵 (1/) nature.com/articles/d4158…
The study: 16 healthy young volunteers with no prior infection or vaccination were inoculated nasally with a low dose of pre-Alpha SARS-CoV-2 strain. Interestingly, only 6 had sustained infection, 3 had transient, and 7 had abortive infection at this dose. (2/) nature.com/articles/s4158…
The three infection outcomes allowed investigation of key features associated with susceptibility vs. resistance. Higher baseline expression of HLA-QA2 mRNA was associated with COVID resistance. Early nasal interferon I response was seen in those with transient infection. (3/)
Preventing infection is the best way to avoid diseases like #PAIS. A new study from our team @tianyangmao, Jooyoung Kim, @marioph13 et al shows that a generic antibiotic neomycin acts on the host immune system in the👃🏽to trigger antiviral resistance. (1/)🧵 pnas.org/doi/10.1073/pn…
This work is inspired by @SmitaGopinath et al who showed that an antibiotic class called aminoglycosides has an unusual antiviral property. Aminoglycosides including neomycin trigger interferon-stimulated genes through a TLR3-dependent mechanism. (2/) ncbi.nlm.nih.gov/pmc/articles/P…
In our current study, we showed that nasal application of neomycin in mice one day before infection reduces viral load and disease burden after the SARS-COV-2 challenge. @tianyangmao (3/)
Delighted to share our latest work on #longCOVID - sex differences in symptoms and immune signatures. Led by @SilvaJ_C @taka_takehiro @wood_jamie_1 et al. with @LeyingGuan & @PutrinoLab. We find a striking inverse correlation btw testosterone levels and symptom burden👇🏼 (1/)
This work leverages data from our recent Mount Sinai-Yale long COVID "MY-LC" study with the @PutrinoLab. This time, we asked the question, "Are there differences in symptoms and immune signatures of ♀️ vs. ♂️ with LC"? (2/)
While some symptoms were equally frequent in females and males, many were more frequent in females (e.g., swelling, headaches, muscle pain, cramps) than males. The top distinguishing symptoms of LC status by sex were hair loss in females and sexual dysfunction in males. (3/)
In this prospective observational study, we examined changes in symptoms & immune phenotypes in vaccine-naïve people with #LongCovid after COVID-19 vaccination. Due to the timing of the initiation of this study, we were only able to recruit 16 people. However, the insights we gained are intriguing. Led by @connorbgrady, @bornali_27, @silva_JC, @hmkyale et al. (1/) medrxiv.org/content/10.110…
This study was initiated in collaboration with @Survivor_Corps @dianaberrent based on their Facebook poll showing that 40% of respondents with self-reported Long COVID had mild to full symptom resolution after vaccination while 14% reported worsening of their symptoms. (2/) doi.org/10.1101/2021.0…
In addition, evidence from other patient advocate groups, including @patientled and @longCovidSOS, and from @DanielGriffinMD, was emerging at the time on the impact of COVID vaccines in people with long COVID. (3/)
So pleased to report that our Mount Sinai-Yale long COVID (MY-LC) paper with @putrinolab & others is now published!! Proud of the hard work of all who contributed. We found biological signatures that can distinguish people with vs. without #longCOVID (1/) nature.com/articles/s4158…
Question being asked: are there circulating cells & immune factors that are distinct in people with #longCOVID (LC) vs. those who recovered from COVID (convalescent control; CC) or those who never had COVID (healthy control; HC)? We studied 268 participants to address this. (2/)
Most participants were infected during the first wave in 2020, and studied on average about a year after the infection. Most were not hospitalized at acute phase and ~2/3 were female. We examined plasma factors, blood leukocytes & antibodies to SARS2, other viruses & self (3/)