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

Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) - the causal agent in COVID-19 - affects olfaction directly, by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing demonstrated that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing revealed that ACE2 is expressed in support cells, stem cells, and perivascular cells, rather than in neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally-located olfactory epithelial sustentacular cells and olfactory bulb pericytes in the mouse. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients.This article is available to RD&E staff via NHS OpenAthens. Click on the Publisher URL, and log in with NHS OpenAthens if prompted.R01 DC016859/DC/NIDCD NIH HHS/United States R01 DC016222/DC/NIDCD NIH HHS/United States R01 DC014423/DC/NIDCD NIH HHS/United States R011DC016222/NH/NIH HHS/United States U19 NS112953/NS/NINDS NIH HHS/United States F31 DC019017/DC/NIDCD NIH HHS/United States MRC_/Medical Research Council/United Kingdom R01 DC007235/DC/NIDCD NIH HHS/United States R01 DC016224/DC/NIDCD NIH HHS/United States P30 NS072030/NS/NINDS NIH HHS/United Statespublished versio