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Persistent SARS-CoV-2 Effects Induce Neuropathy Signature in Dorsal Root Ganglia Underlying Hypersensitivity in a Hamster Model

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 Nav 1.6-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.

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