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Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

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Title:Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells
Creators Name:Muus, C. and Luecken, M.D. and Eraslan, G. and Waghray, A. and Heimberg, G. and Sikkema, L. and Kobayashi, Y. and Vaishnav, E.D. and Subramanian, A. and Smilie, C. and Jagadeesh, K. and Thu Duong, E. and Fiskin, E. and Torlai Triglia, E. and Ansari, M. and Cai, P. and Lin, B. and Buchanan, J. and Chen, S. and Shu, J. and Haber, A.L. and Chung, H. and Montoro, D.T. and Adams, T. and Aliee, H. and Allon, S.J. and Andrusivova, A.Z. and Angelidis, I. and Ashenberg, O. and Bassler, K. and Bécavin, C. and Benhar, I. and Bergenstråhle, J. and Bergenstråhle, L. and Bolt, L. and Braun, E. and Bui, L.T. and Chaffin, M. and Chichelnitskiy, E. and Chiou, J. and Conlon, T.M. and Cuoco, M.S. and Deprez, M. and Fischer, D.S. and Gillich, A. and Gould, J. and Guo, M. and Gutierrez, A.J. and Habermann, A.C. and Harvey, T. and He, P. and Hou, X. and Hu, L. and Jaiswal, A. and Jiang, P. and Kapellos, T. and Kuo, C.S. and Larsson, L. and Leney-Greene, M.A. and Lim, K. and Litviňuková, M. and Lu, J. and Ludwig, L.S. and Luo, W. and Maatz, H. and Madissoon, E. and Mamanova, L. and Manakongtreecheep, K. and Marquette, C.H. and Mbano, I. and McAdams, A.M. and Metzger, R.J. and Nabhan, A.N. and Nyquist, S.K. and Penland, L. and Poirion, O.B. and Poli, S. and Qi, C.C. and Queen, R. and Reichart, D. and Rosas, I. and Schupp, J. and Sinha, R. and Sit, R.V. and Slowikowski, K. and Slyper, M. and Smith, N. and Sountoulidis, A. and Strunz, M. and Sun, D. and Talavera-López, C. and Tan, P. and Tantivit, J. and Travaglini, K.J. and Tucker, N.R. and Vernon, K. and Wadsworth, M.H. and Waldman, J. and Wang, X. and Yan, W. and Zhao, W. and Ziegler, C.G.K.
Abstract:The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, creates an urgent need for identifying molecular mechanisms that mediate viral entry, propagation, and tissue pathology. Cell membrane bound angiotensin-converting enzyme 2 (ACE2) and associated proteases, transmembrane protease serine 2 (TMPRSS2) and Cathepsin L (CTSL), were previously identified as mediators of SARS-CoV2 cellular entry. Here, we assess the cell type-specific RNA expression of ACE2, TMPRSS2, and CTSL through an integrated analysis of 107 single-cell and single-nucleus RNA-Seq studies, including 22 lung and airways datasets (16 unpublished), and 85 datasets from other diverse organs. Joint expression of ACE2 and the accessory proteases identifies specific subsets of respiratory epithelial cells as putative targets of viral infection in the nasal passages, airways, and alveoli. Cells that co-express ACE2 and proteases are also identified in cells from other organs, some of which have been associated with COVID-19 transmission or pathology, including gut enterocytes, corneal epithelial cells, cardiomyocytes, heart pericytes, olfactory sustentacular cells, and renal epithelial cells. Performing the first meta-analyses of scRNA-seq studies, we analyzed 1,176,683 cells from 282 nasal, airway, and lung parenchyma samples from 164 donors spanning fetal, childhood, adult, and elderly age groups, associate increased levels of ACE2, TMPRSS2, and CTSL in specific cell types with increasing age, male gender, and smoking, all of which are epidemiologically linked to COVID-19 susceptibility and outcomes. Notably, there was a particularly low expression of ACE2 in the few young pediatric samples in the analysis. Further analysis reveals a gene expression program shared by ACE2(+)TMPRSS2(+) cells in nasal, lung and gut tissues, including genes that may mediate viral entry, subtend key immune functions, and mediate epithelial-macrophage cross-talk. Amongst these are IL6, its receptor and co-receptor, IL1R, TNF response pathways, and complement genes. Cell type specificity in the lung and airways and smoking effects were conserved in mice. Our analyses suggest that differences in the cell type-specific expression of mediators of SARS-CoV-2 viral entry may be responsible for aspects of COVID-19 epidemiology and clinical course, and point to putative molecular pathways involved in disease susceptibility and pathogenesis.
Keywords:Animals, Mice
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.04.19.049254
Date:21 April 2020
Additional Information:Norbert Hübner and Roland Schwarz are co-investogators within the HCA Lung Biological Network. Corresponding authors: lung@humancellatlas.org, hca@humancellatlas.org
Official Publication:https://doi.org/10.1101/2020.04.19.049254

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