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

NHLBI LungMap Consortium, Human Cell Atlas Lung Biological Network, Christoph Muus, Malte D Luecken, Gökcen Eraslan, Lisa Sikkema, Avinash Waghray, Graham Heimberg, Yoshihiko Kobayashi, Eeshit Dhaval Vaishnav, Ayshwarya Subramanian, Christopher Smillie, Karthik A Jagadeesh, Elizabeth Thu Duong, Evgenij Fiskin, Elena Torlai Triglia, Meshal Ansari, Peiwen Cai, Brian Lin, Justin BuchananSijia Chen, Jian Shu, Adam L Haber, Hattie Chung, Daniel T Montoro, Taylor Adams, Hananeh Aliee, Samuel J Allon, Zaneta Andrusivova, 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 S E Cuomo, Marie Deprez, Grant Duclos, Denise Fine, David S Fischer, Yan Hu, CanCan Qi

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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.

Original languageEnglish
Pages (from-to)546-559
Number of pages14
JournalNature Medicine
Issue number3
Publication statusPublished - Mar-2021


  • Adult
  • Aged
  • Aged, 80 and over
  • Alveolar Epithelial Cells/metabolism
  • Angiotensin-Converting Enzyme 2/genetics
  • COVID-19/epidemiology
  • Cathepsin L/genetics
  • Datasets as Topic/statistics & numerical data
  • Demography
  • Female
  • Gene Expression Profiling/statistics & numerical data
  • Host-Pathogen Interactions/genetics
  • Humans
  • Lung/metabolism
  • Male
  • Middle Aged
  • Organ Specificity/genetics
  • Respiratory System/metabolism
  • SARS-CoV-2/physiology
  • Sequence Analysis, RNA/methods
  • Serine Endopeptidases/genetics
  • Single-Cell Analysis/methods
  • Virus Internalization

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