Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

Abstract

Recent reports suggest an association between COVID-19 and altered olfactory function. Here we analyze bulk and single cell RNA-Seq datasets to identify cell types in the olfactory epithelium that express molecules that mediate infection by SARS-CoV-2 (CoV-2), the causal agent in COVID-19. We find in both mouse and human datasets that olfactory sensory neurons do not express two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. In contrast, olfactory epithelial support cells and stem cells express both of these genes, as do cells in the nasal respiratory epithelium. Taken together, these findings suggest possible mechanisms through which CoV-2 infection could lead to anosmia or other forms of olfactory dysfunction.

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

“…Direct viral invasion of SARS-CoV and MERS-CoV is observed in multiple brain regions in human patients and mouse models 124,125 , consistent with widespread ACE2 expression in numerous brain cell types. Furthermore, SARS-CoV has been shown to infiltrate the brain via the olfactory epithelium-olfactory bulb axis 127 ; olfactory transmission for SARS-CoV-2 has been recently proposed 128 . Other possible transmission routes could be through the infection of ACE2 + TMPRSS2 + enteric neurons synapsing with vagal afferents, or entry through blood-CNS interfaces such as the choroid plexus or meninges 121,[129][130][131] .…”

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms

“…Prior experimental studies of coronavirus have demonstrated that infection with human alphacoronavirus (HCoV-229E) disrupts ciliary nasal epithelium (Chilvers et al, 2001), a possible mechanism of olfactory dysfunction. Indeed, olfactory epithelial cells express the CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), yet the precise cellular subtype that may mediate anosmia in COVID-19 remains unclear (Brann et al, 2020). For both olfactory and gustatory perception, CoV-2 infiltration of higher-order structures within the CNS, or cranial nerves such as the vagus nerve, involved in signal transduction and chemosensory processing, may underlie their dysfunction (Bromley, 2019).…”

Letter to the Editor Regarding the Viewpoint “Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host–Virus Interaction, and Proposed Neurotropic Mechanism”

“…11 A detailed study of nasal epithelium did not show TMPRSS2 presence in the neuronal component but did on the respiratory epithelium. 12 Notably, SARS-CoV was confirmed in postmortem neurons and glial cells of human patients with fatal systemic manifestations. 13 A non-peer-reviewed report claims there was a case of symptomatic encephalitis with detected SARS-CoV-2 in cerebrospinal fluid.…”