In a recent article in the journal Immunologyresearchers in the United States conducted a longitudinal cohort study in a golden hamster model to investigate mechanisms of sensory alteration induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection compared to influenza A virus (IAV).
Stady: Predictors of long-term neutralizing antibody titers after COVID-19 vaccination with three types of vaccines: the BOOST study.. Image credit: Numstocker / Shutterstock
Characterizing the molecular basis of the effects of SARS-CoV-2 infection on the sensory nervous system could aid in the development of new therapies for pain associated with prolonged coronavirus disease (COVID) and other neurological issues, such as neuropathy and myalgia. Prolonged COVID, also known as post-acute sequelae of SARS-CoV-2, is the persistence of COVID-19-like symptoms two months after recovery, which an alternative diagnosis fails to explain.
Many patients with mild and severe COVID-19 often experience sensory-related symptoms, such as headache, neuropathic and visceral pain, and in rare cases, Guillain-Barre syndrome (GBS) and neuritis. These symptoms usually disappear after infection clears up in most patients but persist into the subacute or chronic time points for many other patients. However, studies have hardly explored the mechanisms by which SARS-CoV-2 triggers these abnormal physical sensitizations.
Dorsal root ganglia (DRGs) are sites of active viral replication and satellite-mediated sequestration. Therefore, in this study, the authors longitudinally evaluated gene expression changes in the sensory tissues of the spinal cord (SC) and cervical and thoracic regions of DRGs from a Syrian golden hamster model after infection with SARS-CoV-2 and IAV and their association with mechanical hypersensitivity. .
They harvested these tissues at one, four, seven, and 14 days post infection (dpi) in the SARS-CoV-2 and IAV infected test groups. Next, they used quantitative reverse transcription polymerase chain reaction (qPCR) to assess the presence of SARS-CoV-2 (NC) protein transcripts and type I interferon (IFN-I)-catalysts of canonical Isg15. Furthermore, the researchers used RNAscope in situ hybridization technology to determine whether SARS-CoV-2 copies localized to specific cell types in DRGs on a single dpi.
The team also performed a neutral test on hamsters infected with IAV or SARS-CoV-2 versus mock-infected hamsters. Evaluation of mechanical withdrawal thresholds during the acute infection phase, that is, between one and four dpi, helped to determine the effects of active and calming viral RNA and IFN-I response on somatosensitization. Furthermore, the researchers performed transcriptional profiling and canonical pathway prediction of Ingenuity Pathway Analysis (IPA) on the RNA-seq data.
The authors found transcripts of SARS-CoV-2 but not their infectious material in the sensory tissues of the cervix and thorax and DRGs of infected animals within the first 24 hours of intranasal infection. Compared to animals infected with IAV, hamsters infected with SARS-CoV-2 showed mild but prolonged mechanical hypersensitivity.
RNA sequencing analysis indicated perturbation of type I IFN-γ signaling in IAV-infected animals and neuronal signaling in SARS-CoV-2-infected animals over a period of 1–4 dpi. Strikingly, neuronal histology appeared in thoracic DRGs from SARS-CoV-2-infected animals 31 days after infection, which coincided with SARS-CoV-2-specific mechanical hypersensitivity.
These data indicate and describe transcriptional signatures in the DRGs of SARS-CoV-2-infected hamsters governing short- and long-term sensory aberrations. It appears to be a potential target for pain management, including the previously validated RNA-binding protein ILF3 in murine pain models.
Sensitivity to IAV-induced mechanical hypersensitivity completely declined at 1 dpi, but SARS-CoV-2-induced hypersensitivity gradually declined, with withdrawal thresholds reaching significance at four dpi, although IAV-induced hypersensitivity IAV was more pronounced than that caused by SARS-CoV-2 in the same period.
Differential gene expression analysis (GEA) of the RNA-seq data revealed transcriptional changes in the DRGs of SARS-CoV-2 and IAV-infected hamsters at different time points. SARS-CoV-2 infection caused more robust differential gene expression at both time points: 344 and 63 genes at one and four dpi, respectively, whereas IAV infection caused 82 and 18 genes to be differentially expressed at one and four time points. dots per inch, respectively. Perhaps the transcriptional changes induced by SARS-CoV-2 counteract interferonisil-induced somatosensitization by adopting a more robust neuronal gene signature.
The pathways most enriched in SARS-CoV-2-infected hamster tissues at one dpi were axonal guidance, synaptic signaling, and neuroinflammation signaling at four dpi. For IAV-infected tissue samples, the higher canonical pathway represents the general viral response pathways. The IPA analysis also showed neuron-specific transcriptional differences within the most up-regulated canonical pathways based on genes with statistical significance p < 0.05.
This study demonstrated the relevance of the SARS-CoV-2 respiratory infection hamster model as a preclinical chronic pain model, which, therefore, in the future, can help in the evaluation of drug therapies. The model is consistent with the acute and chronic somatosensory course of many patients with COVID-19.
In addition, it has helped identify underlying mechanisms across pain models while providing insights into virus-mediated nociceptive states relevant to drug development.