Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
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Abstract
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.
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SciScore for 10.1101/2020.03.25.009084: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Organisms/Strains Sentences Resources Mouse HBC lineage Smart-Seq2 dataset: Single-cell RNA-seq data from HBC-derived cells from Fletcher et al. and Gadye et al (32, 64), labeled via Krt5-CreER driver mice, were downloaded from GEO at accession GSE99251 using the file “GSE95601_oeHBCdiff_Cufflinks_eSet_counts_table.txt.gz”. Krt5-CreERsuggested: NoneExpression data from dorsal horn neurons obtained from C57/BL6 wild type mice, vGat-cre-tdTomato and vGlut2-eGFP mouse lines was used from the spinal cord dataset. C57/BL6suggested: NonevGlut2-eGFPsuggested: NoneSoftware and Algorithms Sentences Resources Human nasal … SciScore for 10.1101/2020.03.25.009084: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Organisms/Strains Sentences Resources Mouse HBC lineage Smart-Seq2 dataset: Single-cell RNA-seq data from HBC-derived cells from Fletcher et al. and Gadye et al (32, 64), labeled via Krt5-CreER driver mice, were downloaded from GEO at accession GSE99251 using the file “GSE95601_oeHBCdiff_Cufflinks_eSet_counts_table.txt.gz”. Krt5-CreERsuggested: NoneExpression data from dorsal horn neurons obtained from C57/BL6 wild type mice, vGat-cre-tdTomato and vGlut2-eGFP mouse lines was used from the spinal cord dataset. C57/BL6suggested: NonevGlut2-eGFPsuggested: NoneSoftware and Algorithms Sentences Resources Human nasal scSeq dataset: Human scSeq data from Durante et al. (37) was downloaded from the GEO at accession GSE139522 Human nasal scSeqsuggested: NoneResults from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:We note several caveats that temper our conclusions. Although current data suggest that ACE2 is the most likely receptor for CoV-2 in vivo, it is possible (although it has not yet been demonstrated) that other molecules such as BSG may enable CoV-2 entry independently of ACE2 (Figures 2E, S3C, S4E, S5A) (55, 56). In addition, it has recently been reported that low level expression of ACE2 can support CoV-2 cell entry (57); it is possible, therefore, that ACE2 expression beneath the level of detection in our assays may yet enable CoV-2 infection of apparently ACE2 negative cell types. We also propose that damage to the olfactory system is either due to primary infection or secondary inflammation; it is possible (although has not yet been demonstrated) that cells infected with CoV-2 can form syncytia with cells that do not express ACE2. Such a mechanism could damage neurons adjacent to infected cells. Any reasonable pathophysiological mechanism for COVID-19-associated anosmia must account for the high penetrance of smell disorders relative to endemic viruses, the apparent suddenness of smell loss (which can precede the development of other symptoms), and the transient nature of dysfunction in many patients (8–12) (11, 13–15); definitive identification of the disease mechanisms underlying COVID-19-mediated anosmia will require additional research. Nonetheless, our identification of cells in the OE and OB expressing molecules known to be involved in CoV-2 entry illuminates a path...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 6. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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Excerpt
How does COVID19 take away your sense of smell? It’s not the neurons in the nose and brain but the support cells that are likely to cause anosmia in COVID-19 patients.
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