Here, we chart the cell-type-specific expression patterns of ACE2 and accessory proteases by integrated analysis of 116 single-cell and single-nucleus RNA-sequencing (scRNA-seq and snRNA-seq) studies, including 31 studies of the lung and airways, and 85 studies of other diverse tissues. 13, 14), most notably nasal goblet cells and multiciliated cells 13 in the airways and AT2 cells in the distal lung 13, 15, 16, and identified ACE2 and TMPRSS2 expression in colonic enterocytes 13, 17. Early analyses of HCA data revealed that some of the cells of the nasal passages, airways, lung parenchyma and gut express ACE2 and TMPRSS2 (refs. The Human Cell Atlas (HCA) community has generated single-cell atlases of diverse tissues in healthy individuals, which can now be leveraged to enable such studies. Identifying specific cell types that can be infected by SARS-CoV-2 and relating SARS-CoV-2 entry factors to key covariates like age or sex could inform our understanding of COVID-19 tropism and heterogeneity in disease outcomes. Finally, adults with preexisting cardiovascular disease may have higher rates of disease acuity and death 2. Smoking may be associated with more severe disease 12. Children are significantly less likely to develop severe acute disease 11. Disease severity and mortality rise with age 9, 10, with a slightly higher incidence and mortality in men 2. There is substantial variation in the clinical consequences of infection across individuals, from asymptomatic illness to death. Viral infection further requires proteolytic cleavage of the S protein, and TMPRSS2 or cathepsin L, encoded by the CTSL gene, can provide this role for cellular entry 8. ACE2 expression has been correlated with increased viral load in human cell lines 5, 6 and in mice 7. Virion infection of host cells is initiated by the viral spike (S) protein binding to ACE2. SARS-CoV-2 RNA has been found in nasal and throat secretions, saliva and stool specimens 4. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.Ĭoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, can manifest with pathologies in multiple systems, including the lungs and airways, gastrointestinal tract, kidney, liver and heart, and multi-organ failure 1, 2, 3. Expression programs shared by ACE2 + TMPRSS2 + cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial–macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways.
Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. Nature Medicine volume 27, pages 546–559 ( 2021) Cite this articleĪngiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body.
The Human Cell Atlas Lung Biological Network.Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics
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