Characterizing the Functional Architecture of the Necklace Olfactory System

AbstractSARS-CoV-2 (CoV-2) is a pandemic coronavirus that causes the COVID-19 syndrome, whichcan include upper respiratory infection (URI) symptoms, severe respiratory distress, acutecardiac injury and death. Clinical reports suggest that infection with CoV-2 is associated withhigh rates of disturbances in smell and taste perception, including anosmia. While many virusesinduce transient changes in odor perception due to inflammatory responses, in at least somecases COVID-related anosmia has been reported to occur in the absence of significant nasalinflammation or coryzal symptoms. This observation suggests that CoV-2 might directly targetodor processing mechanisms, although the specific means through which CoV-2 alters odorperception remains unknown. As part of a paper we recently posted to bioRxiv, we queried bothnew and previously published bulk RNA-Seq and scSeq datasets from the olfactory system forexpression of Ace2, Tmprss2 and other genes implicated in coronavirus entry. This analysisrevealed that in mouse and human olfactory epithelium ACE2 transcripts are absent fromolfactory sensory neurons but present in both sustentacular cells and horizonal basal cells. Weperformed a similar analysis in mouse olfactory bulb, which revealed that neurons fail to expressAce2 (either in the olfactory bulb or in the rest of the brain), but that high levels of Ace2expression are observed in vascular pericytes. These preliminary data suggest that non-neuronal cell types are the primary target of SARS-CoV2, and represent the likely mechanismthrough which the virus causes anosmia. However, these preliminary data are based uponsingle cell sequencing, which is biased in terms of the cell types captured, under-representsgene expression, and fails to identify the distribution of Ace2 protein (which is the relevantmolecule for SARS-CoV-2 entry). Here we request supplementary funding to perform in situ,immunohistochemistry and single cell sequencing experiments to comprehensively characterizethe expression of Ace2 and other SARS-CoV-2 entry genes in all cell types in the olfactorysystem. The results of these experiments will have significant implications for our understandingof disease mechanisms, and represents a key first step towards developing strategies foraddressing any long-term olfactory-related sequelae of SARS-CoV-2.