The Cellular basis of loss of smell in 2019-nCoV-infected individuals

Abstract

A prominent clinical symptom of 2019-novel coronavirus (nCoV) infection is hyposmia/anosmia (decrease or loss of sense of smell), along with general symptoms such as fatigue, shortness of breath, fever and cough. The identity of the cell lineages that underpin the infection-associated loss of olfaction could be critical for the clinical management of 2019-nCoV-infected individuals. Recent research has confirmed the role of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) as key host-specific cellular moieties responsible for the cellular entry of the virus. Accordingly, the ongoing medical examinations and the autopsy reports of the deceased individuals indicate that organs/tissues with high expression levels of ACE2, TMPRSS2 and other putative viral entry-associated genes are most vulnerable to the infection. We studied if anosmia in 2019-nCoV-infected individuals can be explained by the expression patterns associated with these host-specific moieties across the known olfactory epithelial cell types, identified from a recently published single-cell expression study. Our findings underscore selective expression of these viral entry-associated genes in a subset of sustentacular cells (SUSs), Bowman’s gland cells (BGCs) and stem cells of the olfactory epithelium. Co-expression analysis of ACE2 and TMPRSS2 and protein–protein interaction among the host and viral proteins elected regulatory cytoskeleton protein-enriched SUSs as the most vulnerable cell type of the olfactory epithelium. Furthermore, expression, structural and docking analyses of ACE2 revealed the potential risk of olfactory dysfunction in four additional mammalian species, revealing an evolutionarily conserved infection susceptibility. In summary, our findings provide a plausible cellular basis for the loss of smell in 2019-nCoV-infected patients.

The olfactory nerve is not a likely route to brain infection in COVID-19: a critical review of data from humans and animal models

“…To assess whether olfactory receptor neurons may be susceptible to infection by SARS-CoV-2, investigators have determined which cell types in the olfactory epithelium express the obligatory entry proteins for the new coronavirus, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2). These gene and protein expression studies were performed by RNAseq of identified cell types, or using markers for distinct cell types within the olfactory epithelium combined with gene or protein expression for ACE2 and TMPRSS2 [ 6 , 8 , 11 , 23 , 38 , 42 , 52 , 66 , 98 , 103 , 106 ]. The large majority of these studies concluded that sustentacular cells (the primary support cells in the olfactory epithelium) and cells in Bowman’s glands express the virus entry proteins, while all human studies and the majority of animal studies reported that olfactory receptor neurons do not express ACE2, or express ACE2 only very rarely (Tables 1 , 2 and 3 ).…”

Olfactory Rod Cells: A Rare Cell Type in the Larval Zebrafish Olfactory Epithelium With a Large Actin-Rich Apical Projection

“…OSNs project directly to the OB, and thus provide an entry route for pathogens to the brain (reviewed in Dando et al, 2014). Cells in the OE can themselves be damaged by viral infection, leading to a reduction, change, or loss of sense of smell (Brann et al, 2020;Gupta et al, 2020;Kraus et al, 2020). The identification of zebrafish olfactory rod cells, with their unique flexible actin-rich protrusion, offers new opportunities to explore the biology of these cells in a genetically tractable model organism, and thus to understand their contribution to the multimodal sensory functions of the vertebrate olfactory epithelium.…”

Olfactory rod cells: a rare cell type in the larval zebrafish olfactory epithelium with an actin-rich apical projection

“…OSNs project directly to the OB, and thus provide an entry route for pathogens to the brain (reviewed in [Dando et al, 2014]). Cells in the OE can themselves be damaged by viral infection, leading to a reduction, change, or loss of sense of smell, a phenomenon that has attracted much recent attention due to the damaging action of SARS-CoV-2 on the human olfactory system (Brann et al, 2020; Gupta et al, 2020). In the zebrafish, new functions of the OE, such as the detection of sodium and chloride ions (Herrera et al, 2020), continue to be uncovered.…”