Summary There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2 , a tissue-protective mediator during lung injury, to enhance infection. Graphical Abstract Highlights • Meta-analysis of human, non-human primate, and mouse single-cell RNA-seq datasets for putative SARS-CoV-2 targets • Type II pneumocytes, nasal secretory cells, and absorptive enterocytes are ACE2 + TMPRSS2 + • Interferon and influenza increase ACE2 in human nasal epithelia and lung tissue • Mouse Ace2 is not upregulated by interferon, raising implications for disease modeling Analysis of single-cell RNA-seq datasets from human, non-human primate, and mouse barrier tissues identifies putative cellular targets of SARS-CoV-2 on the basis of ACE2 and TMPRSS2 expression. ACE2 represents a previously unappreciated interferon-stimulated gene in human, but not mouse, epithelial tissues, identifying anti-viral induction of a host tissue-protective mechanism, but also a potential means for viral exploitation of the host response.
【저자키워드】 COVID-19, SARS-CoV-2, ACE2, Influenza, Human, interferon, mouse, non-human primate, scRNA-seq, ISG, 【초록키워드】 TMPRSS2, coronavirus, Pathogenesis, Infection, lung, nasal, host response, Lung injury, angiotensin-converting enzyme 2, viral infections, Anti-viral, Protein, Health, cells, clade, target, dataset, cellular entry, ACE2 expression, disease, epithelial, mechanism, SARS-CoV-2 spike, cellular, Pneumocytes, regulate, host proteases, acute respiratory syndrome, Factor, tissue, tissues, transmembrane serine protease, TMPRSS2 expression, lung tissue, upregulation, urgency, type II pneumocytes, interferon-stimulated gene, epithelia, Host, implication, Cell, ENhance, bind, identify, the disease, promote, cause, upregulated, Type, subset, Enterocyte, airway epithelial cell, goblet secretory cells, host tissue, ileal absorptive enterocytes, mouse single-cell RNA-sequencing, raising, single-cell RNA-seq dataset, 【제목키워드】 Specific,