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Persistent SARS-CoV-2 Effects Induce Neuropathy Signature in Dorsal Root Ganglia Underlying Hypersensitivity in a Hamster Model, 2022, Serafini et al

Discussion in 'Long Covid research' started by Andy, May 14, 2022.

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  1. Andy

    Andy Committee Member

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    Abstract

    Post-acute sequelae of COVID-19, commonly known as long-COVID, is defined as a persistent symptom(s) that is unexplainable by alternative diagnosis and lasts beyond three months after the onset of COVID-19. Several studies have now identified long-COVID in >50% of COVID-19 patients, emphasizing the need for elucidating mechanisms underlying these symptoms. Pain is a prevalent symptom in long-COVID patients and presents as headache, persistent muscle pain, joint pain, stomach pain, chest pain, respiratory discomfort, and dysesthesia or paresthesia. Understanding the molecular underpinnings of pain maintenance in these patients could provide information on novel therapeutic strategies. Our lab has previously identified novel treatments for pain due to peripheral inflammation from dysesthesia-inducing mechanisms associated with acute SARS-CoV-2 (SCV2) respiratory infection in hamsters (1-4 days post-infection, dpi). We have also previously demonstrated the validity of long-term infection of hamsters (30-60 dpi) as a pre-clinical model of long-COVID.

    By utilizing the Von Frey assay, we found that SCV2, but not Influenza A, causes mechanical hypersensitivity at 28 dpi in both male and female hamsters. Bulk RNA sequencing of 31 dpi thoracic dorsal root ganglia (DRGs) revealed a unique transcriptional perturbation signature (168 DEGs, 47 up & 121 down, p-adj.<0.1), despite viral clearance at approximately 7 dpi. Ingenuity Pathway Analysis of this sequencing (853 DEGs, p-nom.<0.05) identified several injury-related canonical pathways, including Production of NO & ROS in Macrophages, Signaling by Rho Family GTPases, mTOR Signaling, Estrogen Receptor Signaling, and Ephrin Receptor Signaling. The Enrichr DisGeNET browser associated these transcriptional changes with clinical neurodegeneration phenotypes, including Amyotrophic Lateral Sclerosis, Alzheimer’s Disease, Neurodegenerative Disorders, and Parkinson Disease. Of note, TUNEL staining did not demonstrate any sign of SCV2-induced sensory neuron apoptosis at 31 dpi. Further investigation of the sequencing dataset revealed a broad downregulation of TubbmRNA isoforms and Mbp, suggesting microtubule and myelin dysregulation. We also observed a drastic increase in Scn8areads, which could point to Nav1.6-induced DRG neuron hyperexcitability.

    In conclusion, our findings suggest that SCV2 leaves a lasting hypersensitivity-associated transcriptomic signature in DRGs despite early viral clearance that appears to be associated with neurodegeneration mechanisms. As we continue investigating the mechanisms underlying SCV2-induced actions in DRGs and peripheral nerves, we will also use an upstream regulator analysis of our RNA sequencing data to identify promising therapeutic targets.

    This is the full abstract presented at the Experimental Biology meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract.

    https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R2167
     
    Andy, May 14, 2022
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  2. Hutan

    Hutan Moderator Staff Member

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    "Our lab" All the authors seem to be from Icahn School of Medicine at Mount Sinai, New York, and the abstract is labelled with "Friedman Brain Institute Research Scholars Partnership"

    If I'm understanding that right, they seem to have a hamster model of something like fibromyalgia, with this abstract suggesting it's persisting up to 28 days post-infection with SARS-CoV-2. And, it's affecting both male and female hamsters - they don't mention a sex difference, although perhaps there is one.

    https://en.wikipedia.org/wiki/Dorsal_root_ganglion
    It seems important.

    I'm reminded that a doctor was unable to find knee reflexes in me early on in my illness, despite going to a great deal of effort to find them, but they had returned by the time I got to a neurologist 4 or so months later. I think it could be worth trying to understand the detail of what these authors are reporting. It's a shame there isn't a full paper.
     
    Last edited: May 14, 2022
    Hutan, May 14, 2022
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  3. Hutan

    Hutan Moderator Staff Member

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    Really, this idea that an infection could cause damage, sometimes permanent damage to nerves and so affect body function should not be so strange.

    We know that Covid-19 can affect the sense of smell - resulting in people not being able to smell at all, or changing the perception of odours. It therefore is not surprising that other nerves could be affected, and that it might result in changes in other senses, such as the sense of pressure on skin, and pain.
     
    Hutan, May 15, 2022
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  4. Joan Crawford

    Joan Crawford Senior Member (Voting Rights)

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    Would be great to know more about this.

    Dorsal root ganglionosis has been found on autopsy in small sample size examined in pwME. Kinda don't get why this has not been studied extensively in ME, FMS and other chronic pain conditions.......
     
    Joan Crawford, May 15, 2022
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  5. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    This sounds like gobbledygook to me. If these RNAs indicate a relevant injury process we should see some injury on conventional old fashioned histology - at least a few leucocytes infiltrating maybe?

    I am also doubtful of the relevance of mechanical hypersensitivity. At one time it was said to be the hallmark of fibromyalgia but the it got dropped from the diagnostic process.
     
    Jonathan Edwards, May 16, 2022
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  6. Hutan

    Hutan Moderator Staff Member

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    Fair enough - the abstract seems to be suggesting there are these markers of perturbations in the DRG, but not cell death.

    Would we necessarily see leucocyte infiltration if the dorsal root ganglia are just 'perturbed'? Is there leucocyte infiltration when olfactory nerves are disturbed enough to produce anosmia?
     
    Hutan, May 16, 2022
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  7. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    If nerve cells have got nadgered by viruses there ought at least to be a few NK and T cells around.
    And if they are chucking out RNA related to leucocyte activation that is only 'aha' if there is some leucocyte activation to my mind.

    I have no idea what you find in various causes of anosmia but a thin you are very likely to see some structural change in the nerve endings or cytosol. For something as small as hamster DRGs you do thin resin sections with a range of stains and I would be surprised if there wasn't some sort of structural change if the problem is virus induced.

    There is a big problem these days with people shoving samples through molecular biological screens without having any idea of what to look for in terms of simple structural change. Most lab scientists have no idea where to start to read a section.
     
    Jonathan Edwards, May 17, 2022
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  8. FMMM1

    FMMM1 Senior Member (Voting Rights)

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    When I glanced at this I thought - did microtubule (dysregulation) come up in the small Norwegian ME/CFS genetic (GWAS) study and I think it did --- check out Strategist's post here*

    Of course the Norwegian study was about ME/CFS and this is SARS Covid 2 ---- so I've no idea where I'm going with this post ----

    * https://www.s4me.info/threads/genet...022-hajdarevic-et-al.25070/page-2#post-411286
     
    FMMM1, May 18, 2022
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