Researchers show the effect of SARS-CoV-2 infection on somatosensory abnormalities in a hamster model

In a recent article published in the journal Sciences Immunologyresearchers in the United States performed a longitudinal cohort study in a golden hamster model to investigate the mechanisms of sensory impairment induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared to an influenza A virus (IAV).

Study: Predictors of long-term neutralizing antibody titers after vaccination against COVID-19 by three types of vaccines: the BOOST study. Image Credit: Numstocker/Shutterstock

Background

Characterizing the molecular basis of the effects of SARS-CoV-2 infection on the sensory nervous system could help inform the development of new therapies for pain associated with long-lasting coronavirus disease (COVID) and others neurological problems, such as neuropathy and myalgia. Long COVID, also known as post-acute sequelae of SARS-CoV-2, is the persistence of COVID-19-like symptoms beyond two months after recovery, which alternative diagnosis fails to elucidate. .

Many patients with mild and severe COVID-19 often present with sensory symptoms, such as headache, visceral and nerve pain, and, in rare cases, Guillain-Barré syndrome (GBS) and polyneuritis. These symptoms usually resolve after the infection clears in most patients, but persist at subacute or chronic times in many others. However, studies have barely explored the mechanisms by which SARS-CoV-2 triggers these abnormal somatosensations.

About the study

Dorsal root ganglia (DRGs) are sites of active viral replication and satellite sequestration. Thus, in the present study, researchers longitudinally assessed gene expression changes in sensory tissues of the spinal cord (SC) and cervical and thoracic regions of DRGs of the Syrian golden hamster model after infection with SARS- CoV-2 and IAV and their association with mechanical hypersensitivity.

They harvested these tissues one, four, seven and 14 days post infection (dpi) in the test groups infected with SARS-CoV-2 and IAV. Next, they used quantitative reverse transcription polymerase chain reaction (qPCR) to assess the presence of SARS-CoV-2 nucleocapsid (NC) protein transcripts and canonical Isg15 transcripts stimulated by type interferon I (IFN-I). Additionally, the researchers used the RNAscope in situ hybridization technique to determine whether SARS-CoV-2 transcripts localized to specific cell types in DRGs on a dpi.

The team also performed a monofilament test on hamsters infected with IAV or SARS-CoV-2 compared to hamsters infected with a fake. Assessing mechanical withdrawal thresholds during the acute infection phase, i.e. between one and four dpi, helped them to delineate the effects of active and diminishing viral RNA and IFN response. -I on somatosensation. Additionally, the researchers performed transcriptional profiling and canonical Ingenuity Pathway Analysis (IPA) prediction on the RNA-seq data.

Study results

The authors found SARS-CoV-2 transcripts but not their infectious material in cervical and thoracic SC sensory tissues and DRGs of infected animals within the first 24 hours after intranasal infection. Compared to IAV-infected animals, SARS-CoV-2 infected hamsters exhibited mild but prolonged mechanical hypersensitivity.

RNA sequencing analysis indicated disrupted IFN type I signaling in IAV-infected animals and neuronal signaling in SARS-CoV-2 infected animals for one to four days per inch. Strikingly, a neuropathic transcriptome appeared in thoracic DRGs of SARS-CoV-2 infected animals 31 days post-infection, which coincided with SARS-CoV-2-specific mechanical hypersensitivity.

These data indicate and elucidate the transcriptomic signatures in DRGs of SARS-CoV-2 infected hamsters that govern short- and long-term sensory aberrations. It appears to be a potential target for pain management, including the RNA-binding protein ILF3 previously validated in mouse models of pain.

IAV-induced mechanical hypersensitivity disappeared completely at one dpi, but hypersensitivity triggered by SARS-CoV-2 infection gradually decreased, with withdrawal thresholds reaching significance at four dpi, although l hypersensitivity induced by IAV was more pronounced than that caused by SARS-CoV-2 in the same period.

Differential gene expression analysis (GEA) of RNA-seq data revealed transcriptomic changes in DRGs of SARS-CoV-2 and IAV infected hamsters at different time points. SARS-CoV-2 infection caused more vigorous differential gene expression at both time points: 344 and 63 genes at one and four dpi, respectively, while IAV infection caused 82 and 18 to be differentially expressed genes at one and four dpi, respectively. Perhaps SARS-CoV-2-induced transcriptional changes counteracted IFN-induced somatosensory sensitization by adopting a more vigorous neuronal genetic signature.

The most enriched pathways in SARS-CoV-2 infected hamster tissue at one dpi were axon guidance and synaptogenesis signaling and neuroinflammation signaling at four dpi. For IAV-infected tissue samples, the upper canonical pathway represented the generic viral response pathways. IPA analysis also demonstrated neuron-specific transcriptional variations in the most upregulated canonical pathways based on genes with statistical significance of p<0.05.

conclusion

This study established the relevance of the hamster respiratory infection model of SARS-CoV-2 as a preclinical model of chronic pain, which, thus, in the future, could help to evaluate pharmacological treatments. The model aligned with the acute and chronic somatosensory trajectory of many patients with COVID-19.

Furthermore, it helped to identify basic mechanisms in pain models while providing insights into viral-mediated nociceptive states relevant for drug development.