Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

The novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understandACE2abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressingACE2was low (1.7% overall), alveolar type II (AT2, 2.2%ACE2+) cells exhibited highest levels ofACE2expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed withACE2that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD;HHIP), pneumonia and infection (FGGandC4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably,DMBT1was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated withACE2. We describe a population ofACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g.DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.