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

Nat Med

Authors	Christoph Muus Malte Luecken Gökcen Eraslan Lisa Sikkema Avinash Waghray Graham Heimberg Yoshihiko Kobayashi Eeshit Vaishnav Ayshwarya Subramanian Christopher Smillie Karthik Jagadeesh Elizabeth Duong Evgenij Fiskin Elena Triglia Meshal Ansari Peiwen Cai Brian Lin Justin Buchanan Sijia Chen Jian Shu Adam Haber Hattie Chung Daniel Montoro Taylor Adams Hananeh Aliee Samuel Allon Zaneta Andrusivova Ilias Angelidis Orr Ashenberg Kevin Bassler Christophe Bécavin Inbal Benhar Joseph Bergenstråhle Ludvig Bergenstråhle Liam Bolt Emelie Braun Linh Bui Steven Callori Mark Chaffin Evgeny Chichelnitskiy Joshua Chiou Thomas Conlon Michael Cuoco Anna Cuomo Marie Deprez Grant Duclos Denise Fine David Fischer Shila Ghazanfar Astrid Gillich Bruno Giotti Joshua Gould Minzhe Guo Austin Gutierrez Arun Habermann Tyler Harvey Peng He Xiaomeng Hou Lijuan Hu Yan Hu Alok Jaiswal Lu Ji Peiyong Jiang Theodoros Kapellos Christin Kuo Ludvig Larsson Michael Leney-Greene Kyungtae Lim Monika Litviňuková Leif Ludwig Soeren Lukassen Wendy Luo Henrike Maatz Elo Madissoon Lira Mamanova Kasidet Manakongtreecheep Sylvie Leroy Christoph Mayr Ian Mbano Alexi McAdams Ahmad Nabhan Sarah Nyquist Lolita Penland Olivier Poirion Sergio Poli CanCan Qi Rachel Queen Daniel Reichart Ivan Rosas Jonas Schupp Conor Shea Xingyi Shi Rahul Sinha Rene Sit Kamil Slowikowski Michal Slyper Neal Smith Alex Sountoulidis Maximilian Strunz Travis Sullivan Dawei Sun Carlos Talavera-López Peng Tan Jessica Tantivit Kyle Travaglini Nathan Tucker Katherine Vernon Marc Wadsworth Julia Waldman Xiuting Wang Ke Xu Wenjun Yan William Zhao Carly Ziegler NHLBI LungMap Consortium Human Cell Atlas Lung Biological Network
Keywords	Female Humans Male Gene Expression Profiling Adult Aged Middle Aged Organ Specificity Demography Single-Cell Analysis Sequence Analysis, RNA Host-Pathogen Interactions Aged, 80 and over Datasets as Topic Lung Respiratory System Serine Endopeptidases Virus Internalization COVID-19 SARS-CoV-2 Alveolar Epithelial Cells Angiotensin-Converting Enzyme 2 Cathepsin L
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 ACE2TMPRSS2 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.
Year of Publication	2021
Journal	Nat Med
Volume	27
Issue	3
Pages	546-559
Date Published	2021 03
ISSN	1546-170X
DOI	10.1038/s41591-020-01227-z
PubMed ID	33654293
Links
Grant list	RC2 DK114784 / DK / NIDDK NIH HHS / United States W81XWH1410234 / Department of Defense R01 HL133153 / HL / NHLBI NIH HHS / United States R01 HL141380 / HL / NHLBI NIH HHS / United States U01 HL122700 / HL / NHLBI NIH HHS / United States K01 HL140187 / HL / NHLBI NIH HHS / United States R01 HL145372 / HL / NHLBI NIH HHS / United States R01 HL146557 / HL / NHLBI NIH HHS / United States K08 HL146943 / HL / NHLBI NIH HHS / United States U01 HL148867 / HL / NHLBI NIH HHS / United States U01 HL148856 / HL / NHLBI NIH HHS / United States K08 HL130595 / HL / NHLBI NIH HHS / United States P30 DK043351 / DK / NIDDK NIH HHS / United States U01 HL145550 / HL / NHLBI NIH HHS / United States R01 DK117263 / DK / NIDDK NIH HHS / United States
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