Abstract

There is pressing urgency to better understand the pathogenesis of the severe acute respiratory syndrome (SARS) coronavirus (CoV) clade SARS-CoV-2, which causes the disease known as COVID-19. SARS-CoV-2, like SARS-CoV, utilizes ACE2 to bind host cells. While initial SARS- CoV-2 cell entry and infection depend on ACE2 in concert with the protease TMPRSS2 for spike (S) protein activation, the specific cell subsets targeted by SARS-CoV-2 in host tissues, and the factors that regulate ACE2 expression, remain unknown. Here, we leverage human and non- human primate (NHP) single-cell RNA-sequencing (scRNA-seq) datasets to uncover the tissue- resident cell subsets that may serve as the cellular targets of SARS-CoV-2. We identify ACE2 and TMPRSS2 co-expressing cells within type II pneumocytes in NHP lung, absorptive enterocytes in human and NHP terminal ileum, and human nasal goblet secretory cells. Strikingly, we discover, and extensively corroborate using publicly available data sets, that ACE2 is an interferon-stimulated gene (ISG) in human epithelial cells. We further validate this finding in primary upper airway human respiratory epithelial cells. Thus, SARS-CoV-2 may exploit IFN- driven upregulation of ACE2, a key tissue-protective mediator during lung injury, to enhance infection.