SARS-CoV-2 infects olfactory neurons and basal stem cells and induces axonal degeneration through TRPV1 activation

Summary Neurological complications such as anosmia are among the most frequent and persistent symptoms of COVID-19; yet, the mechanisms linking SARS-CoV-2 infection to sensory neuronal injury remain unclear. We demonstrate that SARS-CoV-2 directly infects olfactory sensory neurons through ACE2 upregulation and stimulates basal stem cell proliferation, as shown in human iPSC-derived sensory neurons and validated in golden Syrian hamsters. Exposure to live viruses or its S1 spike protein induces TRPV1 channel redistribution from the nucleus to the plasma membrane, resulting in axonal degeneration. Single-nucleus RNA sequencing reveals activation of exocytosis and transmembrane transport pathways with disruption of axonal guidance networks. Pharmacological inhibition of TRPV1 with capsazepine mitigates neuronal injury and preserves axonal integrity. These findings identify TRPV1 activation as a central mediator of SARS-CoV-2-induced neurodegeneration in the olfactory epithelium and suggest that TRPV1 antagonism offers a promising therapeutic avenue for treating COVID-19-related anosmia.