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

Han, G.; Sinjab, A.; Treekitkarnmongkol, W.; Brennan, P.; Hara, K.; Chang, K.; Bogatenkova, E.; Sanchez-Espiridion, B.; Behrens, C.; Gao, B.; Girard, L.; Zhang, J.; Sepesi, B.; Cascone, T.; Byers, L.; Gibbons, D. L.; Chen, J.; Moghaddam, S. J.; Ostrin, E. J.; Fujimoto, J.; Shay, J.; Heymach, J. V.; Minna, J. D.; Dubinett, S.; Scheet, P. A.; Wistuba, I. I.; Hill, E.; Telesco, S.; Stevenson, C.; Spira, A. E.; Wang, L.; Kadara, H.

doi:10.1101/2020.04.16.045617

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bioRxiv · 10.1101/2020.04.16.045617

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

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Abstract

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 understand ACE2 abundance 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 expressing ACE2 was low (1.7% overall), alveolar type II (AT2, 2.2% ACE2+) cells exhibited highest levels of ACE2 expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed with ACE2 that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD; HHIP), pneumonia and infection (FGG and C4BPA) 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, DMBT1 was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated with ACE2. We describe a population of ACE2-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.

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Han, G., Sinjab, A., Treekitkarnmongkol, W., Brennan, P., Hara, K., Chang, K., Bogatenkova, E., Sanchez-Espiridion, B., Behrens, C., Gao, B., Girard, L., Zhang, J., Sepesi, B., Cascone, T., Byers, L., Gibbons, D. L., Chen, J., Moghaddam, S. J., Ostrin, E. J., Fujimoto, J., Shay, J., Heymach, J. V., Minna, J. D., Dubinett, S., Scheet, P. A., Wistuba, I. I., Hill, E., Telesco, S., Stevenson, C., Spira, A. E., Wang, L., Kadara, H.. 2020-04-17. 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. https://doi.org/10.1101/2020.04.16.045617

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