SARS-CoV-2 Airway Infection Results in Time-dependent Sensory Abnormalities in a Hamster Model

Abstract

Despite being largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and long-lasting phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster infection model to characterize the effects of SARS-CoV-2 versus Influenza A virus (IAV) infection on the sensory nervous system. Efforts to detect the presence of virus in the cervical/thoracic spinal cord and dorsal root ganglia (DRGs) demonstrated detectable levels of SARS-CoV-2 by quantitative PCR and RNAscope uniquely within the first 24 hours of infection. SARS-CoV-2-infected hamsters demonstrated mechanical hypersensitivity during acute infection; intriguingly, this hypersensitivity was milder, but prolonged when compared to IAV-infected hamsters. RNA sequencing (RNA-seq) of thoracic DRGs from acute infection revealed predominantly neuron-biased signaling perturbations in SARS-CoV-2-infected animals as opposed to type I interferon signaling in tissue derived from IAV-infected animals. RNA-seq of 31dpi thoracic DRGs from SARS-CoV-2-infected animals highlighted a uniquely neuropathic transcriptomic landscape, which was consistent with substantial SARS-CoV-2-specific mechanical hypersensitivity at 28dpi. Ontology analysis of 1, 4, and 30dpi RNA-seq revealed novel targets for pain management, such as ILF3. Meta-analysis of all SARS-CoV-2 RNA-seq timepoints against preclinical pain model datasets highlighted both conserved and unique pro-nociceptive gene expression changes following infection. Overall, this work elucidates novel transcriptomic signatures triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities while also highlighting several therapeutic targets for alleviation of infection-induced hypersensitivity.

Innate immune evasion strategies of SARS-CoV-2

“…Initial efforts to understand long COVID have found evidence for localized and sustained inflammation in the olfactory system, changes in areas of the brain and anomalies in the blood 168 , 195 , 196 . When modelled in small animals, comparable observations further suggest that these events can result in changes to sensory perception, neural biology, renal function and cardiovascular performance 169 , 197 . Although many of these disease manifestations could be stochastic or driven by a common mechanism, at this time we still do not understand the basis of continued inflammation.…”

Viral immunity: Basic mechanisms and therapeutic applications—a Keystone Symposia report

“…RNA sequencing of humans who had recovered from COVID‐19 revealed similar transcriptional changes in the olfactory bulb. These data suggest that persistent olfactory bulb inflammation is a unique feature of SARS‐CoV‐2 infection and may be a factor in long COVID symptoms 6,7 …”

“…These data suggest that persistent olfactory bulb inflammation is a unique feature of SARS-CoV-2 infection and may be a factor in long COVID symptoms. 6,7 Identifying biomarkers of mortality from Lassa fever Jamie Strampe from John Connor's lab at Boston University presented work on identifying a serum protein biomarker of mortality in patients with Lassa fever. In a cohort of approximately 200 patients that spanned three Lassa fever seasons, Strampe identified 18 host proteins that were higher in patients who died of Lassa fever than in those who survived.…”

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

“…6E). The top USRs were (i) PTPRR (a protein tyrosine phosphatase receptor), which was recently identified in a study of brains from SARS-CoV-2 infected hamsters and is associated with depression in humans (Serafini et al, 2022), (ii) COPS5 (COP9 signalosome subunit 5), whose mRNA is bound by SARS-CoV-2 NSP9, perhaps resulting in suppression of host responses (Banerjee et al, 2020), (iii) LARP1, a translational repressor that binds SARS-CoV-2 RNA (Schmidt et al, 2021), (iv) ESR1 (nuclear estrogen receptor), which is important for ACE2 expression (Oner et al, 2022), (v) EGLIN, oxygen sensors that target HIF α subunits for degradation, with HIF-1α promoting SARS-CoV-2 infection and inflammation (Tian et al, 2021). IPA Diseases and Functions feature identified a series of neuropathology-associated annotations, including a motor dysfunction signature, with motor deficits documented for severe COVID-19 patients (Graham et al, 2022).…”