{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T07:26:34Z","timestamp":1770276394501,"version":"3.49.0"},"reference-count":26,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,5]],"date-time":"2021-06-05T00:00:00Z","timestamp":1622851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI127783"],"award-info":[{"award-number":["R01AI127783"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Epithelial characteristics underlying the differential susceptibility of chronic asthma to SARS-CoV-2 (COVID-19) and other viral infections are currently unclear. By revisiting transcriptomic data from patients with Th2 low versus Th2 high asthma, as well as mild, moderate, and severe asthmatics, we characterized the changes in expression of human coronavirus and influenza viral entry genes relative to sex, airway location, and disease endotype. We found sexual dimorphism in the expression of SARS-CoV-2-related genes ACE2, TMPRSS2, TMPRSS4, and SLC6A19. ACE2 receptor downregulation occurred specifically in females in Th2 high asthma, while proteases broadly assisting coronavirus and influenza viral entry, TMPRSS2, and TMPRSS4, were highly upregulated in both sexes. Overall, changes in SARS-CoV-2-related gene expression were specific to the Th2 high molecular endotype of asthma and different by asthma severity and airway location. The downregulation of ACE2 (COVID-19, SARS) and ANPEP (HCoV-229E) viral receptors wascorrelated with loss of club and ciliated cells in Th2 high asthma. Meanwhile, the increase in DPP4 (MERS-CoV), ST3GAL4, and ST6GAL1 (influenza) was associated with increased goblet and basal activated cells. Overall, this study elucidates sex, airway location, disease endotype, and changes in epithelial heterogeneity as potential factors underlying asthmatic susceptibility, or lack thereof, to SARS-CoV-2.<\/jats:p>","DOI":"10.3390\/v13061081","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T22:23:00Z","timestamp":1623104580000},"page":"1081","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Comparative Study of SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E and Influenza Host Gene Expression in Asthma: Importance of Sex, Disease Severity, and Epithelial Heterogeneity"],"prefix":"10.3390","volume":"13","author":[{"given":"Mackenzie E.","family":"Coden","sequence":"first","affiliation":[{"name":"Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucas F.","family":"Loffredo","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiam","family":"Abdala-Valencia","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergejs","family":"Berdnikovs","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jaci.2020.04.006","article-title":"Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan","volume":"146","author":"Li","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.1111\/all.14238","article-title":"Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China","volume":"75","author":"Zhang","year":"2020","journal-title":"Allergy"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1016\/j.jaip.2020.05.006","article-title":"Asthma prolongs intubation in CO VID-19","volume":"8","author":"Mahdavinia","year":"2020","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jaci.2020.04.009","article-title":"Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2","volume":"146","author":"Jackson","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/resp.14003","article-title":"ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma","volume":"26","author":"Wark","year":"2021","journal-title":"Respirology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jaci.2020.05.004","article-title":"Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells","volume":"146","author":"Kimura","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1164\/rccm.200903-0392OC","article-title":"T-helper Type 2\u2013driven Inflammation Defines Major Subphenotypes of Asthma","volume":"180","author":"Woodruff","year":"2009","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/s41591-019-0468-5","article-title":"A cellular census of human lungs identifies novel cell states in health and in asthma","volume":"25","author":"Braga","year":"2019","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"152","DOI":"10.3389\/fpubh.2020.00152","article-title":"Gender Differences in Patients With COVID-19: Focus on Severity and Mortality","volume":"8","author":"Jin","year":"2020","journal-title":"Front. Public Health"},{"key":"ref_10","first-page":"1","article-title":"Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma","volume":"22","author":"Kermani","year":"2021","journal-title":"Respir. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.omtm.2020.05.013","article-title":"Airways Expression of SARS-CoV-2 Receptor, ACE2, and TMPRSS2 Is Lower in Children Than Adults and Increases with Smoking and COPD","volume":"18","author":"Alabed","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13073-021-00866-2","article-title":"Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium","volume":"13","author":"Kasela","year":"2021","journal-title":"Genome Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1164\/rccm.202003-0821OC","article-title":"COVID-19 Related Genes in Sputum Cells in Asthma: Relationship to Demographic Features and Corti-costeroids","volume":"202","author":"Peters","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1097\/INF.0b013e31819d0d27","article-title":"The Pediatric Burden of Human Coronaviruses Evaluated for Twenty Years","volume":"28","author":"Talbot","year":"2009","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.3201\/eid2510.190130","article-title":"Transmissibility of MERS-CoV Infection in Closed Setting, Riyadh, Saudi Arabia, 2015","volume":"25","author":"Alaswad","year":"2019","journal-title":"Emerg. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/j.1399-3038.2004.00137.x","article-title":"Childhood severe acute respiratory syndrome, coronavirus infections and asthma","volume":"15","author":"Chng","year":"2004","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14614","DOI":"10.1128\/JVI.79.23.14614-14621.2005","article-title":"ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differenti-ation of human airway epithelia","volume":"79","author":"Jia","year":"2005","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1016\/j.jaci.2017.04.010","article-title":"Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases","volume":"139","author":"Schleimer","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1002\/jcb.21248","article-title":"Angiotensin converting enzyme 2 is primarily epithelial and is developmentally regulated in the mouse lung","volume":"101","author":"Wiener","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/s41591-020-0868-6","article-title":"SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes","volume":"26","author":"Sungnak","year":"2020","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1164\/rccm.202003-0541OC","article-title":"Expression of the SARS-CoV-2 ACE2 Receptor in the Human Airway Epithelium","volume":"202","author":"Zhang","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.cell.2020.04.035","article-title":"SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues","volume":"181","author":"Ziegler","year":"2020","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Iwata-Yoshikawa, N., Okamura, T., Shimizu, Y., Hasegawa, H., Takeda, M., and Nagata, N. (2019). TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. J. Virol., 93.","DOI":"10.1128\/JVI.01815-18"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hatesuer, B., Bertram, S., Mehnert, N., Bahgat, M.M., Nelson, P.S., P\u00f6hlman, S., and Schughart, K. (2013). Tmprss2 Is Essential for Influenza H1N1 Virus Pathogenesis in Mice. PLOS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003774"},{"key":"ref_25","unstructured":"(2020, September 01). Coronavirus (COVID-19) Related Deaths by Ethnic Group, England and Wales: 2 March 2020 to 10 April 2020. United Kingdom Office for National Statistics, Available online: https:\/\/www.ons.gov.uk\/peoplepopulationandcommunity\/birthsdeathsandmarriages\/deaths\/articles\/coronavirusrelateddeathsbyethnicgroupenglandandwales\/2march2020to10april2020."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1097\/ACI.0b013e3283292207","article-title":"Asthma and Ethnic Minorities: Socieoeconomic Status and Beyond","volume":"9","author":"Forno","year":"2009","journal-title":"Curr. Opin. Allergy Clin. Immunol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/6\/1081\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:11:15Z","timestamp":1760163075000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/6\/1081"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,5]]},"references-count":26,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["v13061081"],"URL":"https:\/\/doi.org\/10.3390\/v13061081","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,5]]}}}