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

Nat Med. 2021 Mar;27(3):546-559. doi: 10.1038/s41591-020-01227-z. Epub 2021 Mar 2.

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • CTSL protein, human
  • Cathepsin L

Grants and funding