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.
| Original language | English (US) |
|---|---|
| Article number | 5139 |
| Journal | Nature communications |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2020 |
Funding
This work was supported by NIH grants (MAS) R01 HL135156, R01 MD010443, R01 HL128439, P01 HL132821, P01 HL107202, R01 HL117004, and DOD Grant W81WH-16-2-0018. The Genes-Environments and Admixture in Latino Americans (GALA II) Study and E.G.B. were supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, the Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, the National Heart, Lung, and Blood Institute (NHLBI) [R01HL117004, R01HL128439, R01HL135156, X01HL134589]; the National Institute of Environmental Health Sciences [R01ES015794]; the National Institute on Minority Health and Health Disparities (NIMHD) [P60MD006902, R01MD010443], the National Human Genome Research Institute [U01HG009080] and the Tobacco-Related Disease Research Program [24RT-0025, 27IR-0030]. M.J.W. was supported by the NHLBI [K01HL140218]. Burchard NIH Support: T32 GM007546, R01 128439, R01 HL141992, R01 HL141845. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Gene-Environment, Admixture and Latino Asthmatics Study” (phs000920) was performed at the New York Genome Center (3R01HL117004-02S3) and the University of Washington Northwest Genomics Center (HHSN268201600032I). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1, U01HL-120393, contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. WGS of part of GALA II was performed by New York Genome Center under The Centers for Common Disease Genomics of the Genome Sequencing Program (GSP) Grant (UM1 HG008901). The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. GSP is funded by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and the National Eye Institute. The authors wish to acknowledge the following GALA II study collaborators: Shannon Thyne, UCSF; Harold J. Farber, Texas Children’s Hospital; Denise Serebrisky, Jacobi Medical Center; Rajesh Kumar, Lurie Children’s Hospital of Chicago; Emerita Brigino-Buenaventura, Kaiser Permanente; Michael A. LeNoir, Bay Area Pediatrics; Kelley Meade, UCSF Benioff Children’s Hospital, Oakland; William Rodríguez-Cintrón, VA Hospital, Puerto Rico; Pedro C. Ávila, Northwestern University; Jose R. Rodríguez-Santana, Centro de Neu-mología Pediátrica; Luisa N. Borrell, City University of New York; Adam Davis, UCSF Benioff Children’s Hospital, Oakland; Saunak Sen, University of Tennessee. The authors acknowledge the families and patients for their participation and thank the numerous health care providers and community clinics for their support and participation in GALA II. In particular, the authors thank the recruiters who obtained the data: Duanny Alva, MD; Gaby Ayala-Rodríguez; Lisa Caine, RT; Elizabeth Castellanos; Jaime Colón; Denise DeJesus; Blanca López; Brenda López, MD; Louis Martos; Vivian Medina; Juana Olivo; Mario Peralta; Esther Pomares, MD; Jihan Quraishi; Johanna Rodríguez; Shahdad Saeedi; Dean Soto; and Ana Taveras. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
