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Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics

2021; Nature Portfolio; Volume: 27; Issue: 3 Linguagem: Inglês

10.1038/s41591-020-01227-z

1546-170X

Christoph Muus, Malte D. Luecken, Gökcen Eraslan, Lisa Sikkema, Avinash Waghray, Graham Heimberg, Yoshihiko Kobayashi, Eeshit Dhaval Vaishnav, Ayshwarya Subramanian, Christopher S. Smillie, Karthik A. Jagadeesh, Thu Elizabeth Duong, Evgenij Fiškin, Elena Torlai Triglia, Meshal Ansari, Peiwen Cai, Brian Lin, Justin Buchanan, Sijia Chen, Jian Shu, Adam L. Haber, Hattie Chung, Daniel T. Montoro, Taylor Adams, Hananeh Aliee, Samuel J. Allon, Žaneta Andrusivová, Ilias Angelidis, Orr Ashenberg, Kevin Baßler, Christophe Bécavin, Inbal Benhar, Joseph Bergenstråhle, Ludvig Bergenstråhle, Liam Bolt, Emelie Braun, Linh T. Bui, Steven Callori, Mark Chaffin, Evgeny Chichelnitskiy, Joshua Chiou, Thomas M. Conlon, Michael S. Cuoco, Anna Cuomo, Marie Deprez, Grant Duclos, Denise Fine, David S. Fischer, Shila Ghazanfar, Astrid Gillich, Bruno Giotti, Joshua Gould, Minzhe Guo, Austin J. Gutierrez, Arun C. Habermann, Tyler Harvey, Peng He, Xiaomeng Hou, Lijuan Hu, Yan Hu, Alok Jaiswal, Lu Ji, Peiyong Jiang, Theodoros Kapellos, Christin S. Kuo, Ludvig Larsson, Michael Leney-Greene, Kyungtae Lim, Monika Litviňuková, Leif S. Ludwig, Soeren Lukassen, Wendy Luo, Henrike Maatz, Elo Madissoon, Lira Mamanova, Kasidet Manakongtreecheep, Sylvie Leroy, Christoph H. Mayr, Ian Mbano, Alexi McAdams, Ahmad N. Nabhan, Sarah K. Nyquist, Lolita Penland, Olivier Poirion, Sergio Poli, Cancan Qi, Rachel Queen, Daniel Reichart, Iván O. Rosas, Jonas C. Schupp, Conor Shea, Xingyi Shi, Rahul Sinha, Rene Sit, Kamil Slowikowski, Michal Slyper, Neal P. Smith, Alex Sountoulidis, Maximilian Strunz, Travis Sullivan, Dawei Sun, Carlos Talavera‐López, Peng Tan, Jessica Tantivit, Kyle J. Travaglini, Nathan R. Tucker, Katherine A. Vernon, Marc H. Wadsworth, Julia Waldman, Xiuting Wang, Ke Xu, Wenjun Yan, William Zhao, Carly G.K. Ziegler, Gail Deutsch, Jennifer Dutra, Kyle J. Gaulton, Jeanne Holden‐Wiltse, Heidie Huyck, Thomas J. Mariani, Ravi Misra, Cory Poole, Sebastian Preißl, Gloria Pryhuber, Lisa M. Rogers, Xin Sun, Allen Wang, Jeffrey A. Whitsett, Yan Xu, Jehan Alladina, Nicholas E. Banovich, Pascal Barbry, Jennifer Beane, Roby P. Bhattacharyya, Katharine E. Black, Alvis Brāzma, Joshua D. Campbell, Christina Schofield, Joseph Collin, Christian Conrad, Kitty de Jong, Tushar Desai, Diane Z. Ding, Oliver Eickelberg, Roland Eils, Patrick T. Ellinor, Alen Faiz, Christine S. Falk, Michael Farzan, Andrew Gellman, Gad Getz, Ian Glass, Anna Greka, Muzlifah Haniffa, Lida P. Hariri, Mark Hennon, Péter Horváth, Norbert Hübner, Deborah T. Hung, Heidie Huyck, William J. Janssen, Dejan Juric, Naftali Kaminski, M. Koenigshoff, Gerard H. Koppelman, Mark A. Krasnow, Jonathan A. Kropski, Malte Kühnemund, Robert Lafyatis, Majlinda Lako, Eric S. Lander, Haeock Lee, Marc E. Lenburg, Charles‐Hugo Marquette, Ross J. Metzger, Sten Linnarsson, Gang Liu, Y. M. Dennis Lo, Joakim Lundeberg, John C. Marioni, Sarah A. Mazzilli, Benjamin D. Medoff, Kerstin B. Meyer, Zhichao Miao, Alexander V. Misharin, Martijn C. Nawijn, Marko Nikolić, Michela Noseda, José Ordovás-Montañés, Gavin Y. Oudit, Dana Pe’er, Joseph E. Powell, Stephen R. Quake, Jayaraj Rajagopal, Purushothama Rao Tata, Emma L. Rawlins, Aviv Regev, Mary E. Reid, Paul A. Reyfman, Kimberly Rieger‐Christ, Mauricio Rojas, Orit Rozenblatt–Rosen, Kourosh Saeb‐Parsy, Christos Samakovlis, Joshua R. Sanes, Herbert B. Schiller, Joachim L. Schultze, Roland F. Schwarz, Ayellet V. Segrè, Max A. Seibold, Christine E. Seidman, J.G. Seidman, Alex K. Shalek, Douglas P. Shepherd, Rahul Sinha, Jason R. Spence, Avrum Spira, Xin Sun, Erik Sundström, Sarah A. Teichmann, Fabian J. Theis, Alexander M. Tsankov, Ludovic Vallier, Maarten van den Berge, Tave A. Van Zyl, Alexandra–Chloé Villani, Astrid Weins, Ramnik J. Xavier, Ali Önder Yildirim, Laure‐Emmanuelle Zaragosi, Darin Zerti, Hongbo Zhang, Kun Zhang, Xiaohui Zhang,

Single-cell and spatial transcriptomics

Angiotensin-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. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. 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 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. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. 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. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention. An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.