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

Guangchun Han; Ansam Sinjab; Warapen Treekitkarnmongkol; Patrick Brennan; Kieko Hara; Kyle Chang; Elena Bogatenkova; Beatriz Sanchez-Espiridion; Carmen Behrens; Boning Gao; Luc Girard; Jianjun Zhang; Boris Sepesi; Tina Cascone; Lauren Byers; Don L. Gibbons; Jichao Chen; Seyed Javad Moghaddam; Edwin J. Ostrin; Junya Fujimoto; Jerry Shay; John V. Heymach; John D. Minna; Steven Dubinett; Paul A. Scheet; Ignacio I. Wistuba; Edward Hill; Shannon Telesco; Christopher Stevenson; Avrum E. Spira; Linghua Wang; Humam Kadara

We found that ACE2-positive compared to ACE2-negative AT2 cells exhibited increased levels of genes with crucial roles and expression features in lung pathological diseases. The hedgehog interacting protein HHIP was not only shown to play important roles in airway branching during lung development 32 , but also single nucleotide polymorphisms of this gene are associated with increased risk for COPD 31 , a pulmonary ailment characterized by chronic inflammation 52 . FGG coding for fibrinogen-gamma was shown to be induced by pro-inflammatory cytokines 34 and to be elevated in lung pneumonia and infection 33 . C4BPA, coding for C4BP and part of the complement system, was found to recognize and bind pneumonia-causing streptococci in the lung epithelium 35, 36 . It is noteworthy that many patients with COVID-19 (e.g. those with severe disease) commonly display the same pathological phenotypes, namely lung inflammation, fibrosis, and pneumonia, linked to those ACE2-co-expressed genes. It is intriguing to suggest that perhaps this small population of ACE2expressing cells may underlie the pathogenesis of severe acute respiratory distress syndrome, pneumonia and respiratory failure in COVID-19 patients. It is important to note that emerging studies are showing that males are disproportionately affected by COVID-19, possibly due to sex-based immunological bias or differences in smoking patterns and prevalence 53 . Also, a recent preprint suggested that smoking causes expansion of ACE2-expressing lung epithelia 42 . Interestingly, several of the ACE2-co-expressed genes we identified (FGG, DMBT1, C4BPA) were elevated in smoker AT2 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.16.045617 doi: bioRxiv preprint cells. Of note, smoking increases lung inflammation and the risk for various lung diseases including interstitial lung fibrosis, pneumonia and COPD 54 . It is plausible that smoking may augment SARS-CoV-2 entry in the lung and COVID-19 pathogenesis, a supposition that warrants future studies.