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

Satria P. Sajuthi, Peter DeFord, Yingchun Li, Nathan D. Jackson, Michael T. Montgomery, Jamie L. Everman, Cydney L. Rios, Elmar Pruesse, James D. Nolin, Elizabeth G. Plender, Michael E. Wechsler, Angel C. Y. Mak, Celeste Eng, Sandra Salazar, Vivian Medina, Eric M. Wohlford, Scott Huntsman, Deborah A. Nickerson, Soren Germer, Michael C. Zody, Gonçalo Abecasis, Hyun Min Kang, Kenneth M. Rice, Rajesh Kumar, Sam Oh, Jose Rodriguez-Santana, Esteban G. Burchard and Max A. Seibold ()
Additional contact information
Satria P. Sajuthi: Center for Genes, Environment, and Health, National Jewish Health
Peter DeFord: Center for Genes, Environment, and Health, National Jewish Health
Yingchun Li: Center for Genes, Environment, and Health, National Jewish Health
Nathan D. Jackson: Center for Genes, Environment, and Health, National Jewish Health
Michael T. Montgomery: Center for Genes, Environment, and Health, National Jewish Health
Jamie L. Everman: Center for Genes, Environment, and Health, National Jewish Health
Cydney L. Rios: Center for Genes, Environment, and Health, National Jewish Health
Elmar Pruesse: Center for Genes, Environment, and Health, National Jewish Health
James D. Nolin: Center for Genes, Environment, and Health, National Jewish Health
Elizabeth G. Plender: Center for Genes, Environment, and Health, National Jewish Health
Michael E. Wechsler: Department of Medicine, National Jewish Health
Angel C. Y. Mak: University of California San Francisco
Celeste Eng: University of California San Francisco
Sandra Salazar: University of California San Francisco
Vivian Medina: Centro de Neumología Pediátrica
Eric M. Wohlford: University of California San Francisco
Scott Huntsman: University of California San Francisco
Deborah A. Nickerson: University of Washington
Soren Germer: New York Genome Center
Michael C. Zody: New York Genome Center
Gonçalo Abecasis: University of Michigan
Hyun Min Kang: University of Michigan
Kenneth M. Rice: University of Washington
Rajesh Kumar: Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University
Sam Oh: University of California San Francisco
Jose Rodriguez-Santana: Centro de Neumología Pediátrica
Esteban G. Burchard: University of California San Francisco
Max A. Seibold: Center for Genes, Environment, and Health, National Jewish Health

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-18781-2

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