SARS-CoV-2 airway infection results in the development of somatosensory abnormalities in a hamster model

Abstract

Although largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and chronic phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster model to characterize and compare the effects of infection with SARS-CoV-2 and influenza A virus (IAV) on the sensory nervous system. We detected SARS-CoV-2 transcripts but no infectious material in the cervical and thoracic spinal cord and dorsal root ganglia (DRGs) within the first 24 hours of intranasal virus infection. SARS-CoV-2–infected hamsters exhibited mechanical hypersensitivity that was milder but prolonged compared with that observed in IAV-infected hamsters. RNA sequencing analysis of thoracic DRGs 1 to 4 days after infection suggested perturbations in predominantly neuronal signaling in SARS-CoV-2–infected animals as opposed to type I interferon signaling in IAV-infected animals. Later, 31 days after infection, a neuropathic transcriptome emerged in thoracic DRGs from SARS-CoV-2–infected animals, which coincided with SARS-CoV-2–specific mechanical hypersensitivity. These data revealed potential targets for pain management, including the RNA binding protein ILF3, which was validated in murine pain models. This work elucidates transcriptomic signatures in the DRGs triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities.

Desipramine induces anti-inflammatory dorsal root ganglion transcriptional signatures in the murine spared nerve injury model

“…Inflammation is a core mechanism underlying hypersensitivity of peripheral sensory neurons, as it is induced by various perturbations including nerve injury ( Yu et al, 2020 ), viral infection ( Serafini et al, 2023b ), and chemical/diabetic ( Hall et al, 2022 , Zhang et al, 2016 ) neuropathies. Our findings were supported by Kremer et al, in which chronic duloxetine (a serotonin-specific reuptake inhibitor) administration alleviated chronic constriction injury-induced mechanical hypersensitivity and downregulated pro-inflammatory signatures, such as TNFα signaling ( Kremer et al, 2018 ).…”

Animal models to study the neurological manifestations of the post-COVID-19 condition

“…The same transcriptomic analysis predicted the contribution of macrophages and Schwann cells, already known to be involved in neuropathic pain and hypersensitivity, to the SARS-CoV-2-induced proinflammatory state. Interestingly, these results were obtained long after viral clearance, suggesting that the presence of viral transcript (but not infectious particles) and type I interferon response in the peripheral nervous system (dorsal root ganglia and spinal cord) during the first 24 h post-inoculation was sufficient to induce persistent maladaptive neuronal responses 58 .…”

The immunobiology of SARS-CoV-2 infection and vaccine responses: potential influences of cross-reactive memory responses and aging on efficacy and off-target effects

“…Reports on neuropathology have been conflicting, with some reporting neuronal invasion and pathology, while other have reported a lack of viral mRNA in the CNS, although neuronal immune activation and tissue damage have been consistently reported ( 19 , 91 , 95 , 96 ). This neuropathology is more representative of human infection than what has been observed in K18 mice, and given similar viral clearance patterns to humans, hamsters have been used to model PASC ( 19 , 96 , 97 ).…”

“…Reports on neuropathology have been conflicting, with some reporting neuronal invasion and pathology, while other have reported a lack of viral mRNA in the CNS, although neuronal immune activation and tissue damage have been consistently reported ( 19 , 91 , 95 , 96 ). This neuropathology is more representative of human infection than what has been observed in K18 mice, and given similar viral clearance patterns to humans, hamsters have been used to model PASC ( 19 , 96 , 97 ). A recent report detailed structural and transcriptional changes to the lungs, kidneys, olfactory bulb, and olfactory epithelium following CoV2 infection in Syrian hamsters, with an elevated inflammatory transcriptional profile being observed in the hamsters’ brains 31 days after initial infection ( 19 ).…”