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

Muus C, Luecken MD, Eraslan G, Sikkema L, Waghray A, Heimberg G, Kobayashi Y, Vaishnav ED, Subramanian A, Smillie C, Jagadeesh KA, Duong ET, Fiskin E, Triglia ET, Ansari M, Cai P, Lin B, Buchanan J, Chen S, Shu J, Haber AL, Chung H, Montoro DT, Adams T, Aliee H, Allon SJ, Andrusivova Z, Angelidis I, Ashenberg O, Bassler K, Becavin C, Benhar I, Bergenstrahle J, Bergenstrahle L, Bolt L, Braun E, Bui LT, Callori S, Chaffin M, Chichelnitskiy E, Chiou J, Conlon TM, Cuoco MS, Cuomo ASE, Deprez M, Duclos G, Fine D, Fischer DS, Ghazanfar S, Gillich A, Giotti B, Gould J, Guo M, Gutierrez AJ, Habermann AC, Harvey T, He P, Hou X, Hu L, Hu Y, Jaiswal A, Ji L, Jiang P, Kapellos TS, Kuo CS, Larsson L, Leney-Greene MA, Lim K, Litvinukova M, Ludwig LS, Lukassen S, Luo W, Maatz H, Madissoon E, Mamanova L, Manakongtreecheep K, Leroy S, Mayr CH, Mbano IM, Mcadams AM, Nabhan AN, Nyquist SK, Penland L, Poirion OB, Poli S, Qi C, Queen R, Reichart D, Rosas I, Schupp JC, Shea C, Shi X, Sinha R, Sit RV, Slowikowski K, Slyper M, Smith NP, Sountoulidis A, Strunz M, Sullivan TB, Sun D, Talavera-Lopez C, Tan P, Tantivit J, Travaglini KJ, Tucker NR, Vernon KA, Wadsworth MH, Waldman J, Wang X, Xu K, Yan W, Zhao W, Ziegler CGK (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 27

Pages Range: 546-559

Journal Issue: 3

DOI: 10.1038/s41591-020-01227-z

Abstract

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.

Involved external institutions

Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Icahn School of Medicine at Mount Sinai United States (USA) (US) Massachusetts General Hospital United States (USA) (US) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) Harvard University United States (USA) (US) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Royal Institute of Technology / Kungliga Tekniska Högskolan (KTH) Sweden (SE) Deutsches Zentrum für Lungenforschung e.V. (DZL) Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) University of Côte d'Azur / Université Côte d'Azur France (FR) Karolinska Institute Sweden (SE) Boston University United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) European Molecular Biology Laboratory (EMBL) Germany (DE) University of Cambridge United Kingdom (GB) Cincinnati Children's Hospital Medical Center United States (USA) (US) Vanderbilt University United States (USA) (US) Translational Genomics Research Institute (TGen) United States (USA) (US) Stanford University United States (USA) (US) Yale University United States (USA) (US) University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Newcastle University United Kingdom (GB) Wellcome Trust Sanger Institute - Genome Research Limited United Kingdom (GB) Africa Health Research Institute (AHRI) South Africa (ZA) Duke University United States (USA) (US) University of Colorado System United States (USA) (US) The Chinese University of Hong Kong (CUHK) China (CN) Charité - Universitätsmedizin Berlin Germany (DE) Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft / Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) Germany (DE) Stockholm University / Stockholms universitet Sweden (SE) Lahey Hospital & Medical Center United States (USA) (US)

How to cite

APA:

Muus, C., Luecken, M.D., Eraslan, G., Sikkema, L., Waghray, A., Heimberg, G.,... Ziegler, C.G.K. (2021). Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nature Medicine, 27(3), 546-559. https://doi.org/10.1038/s41591-020-01227-z

MLA:

Muus, Christoph, et al. "Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics." Nature Medicine 27.3 (2021): 546-559.

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