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

A new study of human olfactory cells has revealed that viral invasion of supportive cells in the nasal cavity might be driving the loss of smell seen in some patients with COVID-19. The findings show that non-neuronal cells in the brain and nose express genes critical for SARS-CoV-2 entry, while neurons do not; therefore, non-neuronal cells are likely to be the primary targets for virus-induced damage leading to loss of smell, or anosmia. Recent investigations into COVID-19-associated anosmia showed that cells from the human upper airway express high levels of receptor genes involved in SARS-CoV-2 entry, suggesting that these respiratory epithelial cells serve as viral reservoirs during CoV-2 infection. However, these studies did not investigate the sheet of cells that line the nasal cavity, called the olfactory epithelium – the first entryway for pathogens before they reach the respiratory epithelium. Using bulk RNA sequencing of human cells from the nasal mucosa, David Brann and colleagues at Harvard Medical School identified cell types in the olfactory epithelium in the nose and the brain’s olfactory bulb that express two key receptor genes involved in SARS-CoV-2 entry, ACE2 and TMPRSS2. Single cell RNA sequencing of these cells and neurons provided the key insight that neither gene was detected in olfactory neurons, but both were highly expressed by support cells, stem cells, and perivascular cells in the nose and brain. Fluorescent staining of ACE2 in olfactory cells in mice confirmed this result and revealed pervasive expression of ACE2 protein in structural support cells of the nose and in cells that wrap around the capillaries of the olfactory bulb. Identifying the mechanisms that underlie the olfactory symptoms of COVID-19 can help lead to new diagnostics for SARS-CoV-2 infection, yield insights into the cellular dynamics of the nose, and propel future treatments for anosmia, the authors say.

Coronavirus cell entry-related genes are expressed at comparable levels
across respiratory and olfactory epithelial datasets

(A) Schematic of the mapping strategy used to identify similar cell types across datasets, applied to a toy example. Each cell type from “Dataset 1” dataset is mapped to cell types from the “Dataset 2”. From left to right: Each Dataset 1 cell voted on its 5 most similar cells in Dataset 2; the total number of votes cast for each Dataset 2 cell type was quantified; and vote totals were Z-scored against 1000 shuffles where cell type labels were permutated. (B) Mapping was performed bi-directionally between the Deprez et al. (41) and Durante et al. (38) datasets, and the mapping Z-scores in each direction are compared. The set of cell type correspondences with high Z-scores (>25) in both directions are colored red (top). The set of cell type correspondences with high bi-directional mappings shown in red in top panel are highlighted in yellow (bottom). (C) Gene expression across cell types and tissues in Durante et al. (top) and Deprez et al. (bottom). Each gene is normalized to its maximum value across all tissues. Gene expression from Durante et al. was normalized to that in Deprez et al. to enable comparisons (see Methods and Figure S3). The tissues correspond to the indicated positions along the airway from nasal to distal lung. ACE2 expression in olfactory HBC and sustentacular cells is comparable to that observed in other cell types in the lower respiratory tract.

Source – American Association for the Advancement of Science