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

TLDR

Urgent research is needed to understand SARS‑CoV‑2 pathogenesis, as the virus uses its spike protein to bind ACE2 and TMPRSS2 for cell entry, yet the specific cell subsets targeted and the regulation of ACE2 expression remain unclear. The study aims to identify tissue‑resident cell subsets that could be targeted by SARS‑CoV‑2. This was achieved by analyzing human, non‑human primate, and mouse single‑cell RNA‑sequencing datasets across health and disease. We identified ACE2 and TMPRSS2 co‑expression in lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet cells, and showed that ACE2 is an interferon‑stimulated gene, implying that interferon‑driven upregulation may enhance viral infection.

Abstract

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.