SARS-CoV-2 Receptor ACE2 is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Enriched in Specific Cell Subsets Across Tissues

Abstract

There is pressing urgency to better understand the pathogenesis of the severe acute respiratory syndrome (SARS) coronavirus (CoV) clade SARS-CoV-2. 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 cell subsets that may serve as cellular targets of SARS-CoV-2. We identify ACE2/TMPRSS2 co-expressing cells within type II pneumocytes, absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discover that ACE2 is an interferon-stimulated gene (ISG) in human barrier tissue epithelial cells. Thus, SARS-CoV-2 may exploit IFN-driven upregulation of ACE2, a key tissue-protective mediator during lung injury, to enhance infection.

Keywords: SARS-CoV-2, single-cell RNA-sequencing, ACE2, interferon, interferon stimulated gene, barrier tissues, human, non-human primate, epithelial tissues, host-pathogen