Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium

• Published in: Nature communications Vol. 11; no. 1; pp. 5139 - 18
• Main Authors: Sajuthi, Satria P., DeFord, Peter, Li, Yingchun, Jackson, Nathan D., Montgomery, Michael T., Everman, Jamie L., Rios, Cydney L., Pruesse, Elmar, Nolin, James D., Plender, Elizabeth G., Wechsler, Michael E., Mak, Angel C. Y., Eng, Celeste, Salazar, Sandra, Medina, Vivian, Wohlford, Eric M., Huntsman, Scott, Nickerson, Deborah A., Germer, Soren, Zody, Michael C., Abecasis, Gonçalo, Kang, Hyun Min, Rice, Kenneth M., Kumar, Rajesh, Oh, Sam, Rodriguez-Santana, Jose, Burchard, Esteban G., Seibold, Max A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2020; Nature Portfolio
• Subjects: 13/106; 38; 38/91; 631/208/200; 631/337/2019; 631/80/304; 692/699/255/2514; Angiotensin-Converting Enzyme 2; Betacoronavirus - physiology; Child; Coronavirus Infections - metabolism; Coronavirus Infections - pathology; Coronavirus Infections - virology; COVID-19; Epithelial Cells - metabolism; Gene Expression Profiling; Gene Expression Regulation; Genetic Variation; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Inflammation; Interferons - metabolism; Interleukin-13 - metabolism; Middle Aged; multidisciplinary; Nasal Mucosa - metabolism; Nasal Mucosa - pathology; Pandemics; Peptidyl-Dipeptidase A - genetics; Peptidyl-Dipeptidase A - metabolism; Pneumonia, Viral - metabolism; Pneumonia, Viral - pathology; Pneumonia, Viral - virology; SARS-CoV-2; Science; Science (multidisciplinary); Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Virus Internalization
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18781-2

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2 , that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2 . Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes. ACE2 and TMPRSS2 have received recent attention as entry factors for SARS-CoV-2. Here the authors analyze nasal airway transcriptome data from 695 children determining ACE2 and TMPRSS2 expression is induced by viral and type2 inflammation, respectively, and both exhibit eQTLs that vary across world populations.