IL-13 protects epithelial cells from SARS-CoV-2 infection by inhibiting ACE2-mediated virus binding and cell entry

DOI record: { "DOI": "10.1093/immhor/vlaf056", "ISSN": [ "2573-7732" ], "URL": "http://dx.doi.org/10.1093/immhor/vlaf056", "abstract": "<jats:title>Abstract</jats:title>\n <jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preferentially infects airway epithelial cells. This infection is mediated by the binding of SARS-CoV-2 spike (S) protein to ACE2 expressed on target cells. Patients with allergic (type-2) asthma have been reported to be less susceptible to coronavirus disease 2019 (COVID-19), but these effects are controversial and mechanistically unclear. We previously showed lower expression of ACE2 mRNA in airway epithelial cells from type-2 asthmatics compared to healthy donors. Moreover, we and others demonstrated that the type-2 cytokine interleukin 13 (IL-13) suppresses ACE2 expression and SARS-CoV-2 infection in human epithelial cells. To better understand the relationship between type-2 inflammation, ACE2 expression, and SARS-CoV-2 infection, we investigated the effects of IL-13 on critical steps of epithelial cell infection by SARS-CoV-2: S protein-mediated binding to ACE2 on epithelial cells, and ACE2-mediated SARS-CoV-2 entry into these cells. Recombinant IL-13 significantly inhibited both these processes. This inhibition appeared to be mediated by IL-13-induced suppression of ACE2 transcription because IL-13 failed to affect S protein-mediated viral entry into cells that express ACE2 under the control of an IL-13 unresponsive heterologous promoter. We propose that IL-13 protects epithelial cells from SARS-CoV-2 infection largely by inhibiting ACE2 expression and ACE2-mediated downstream events that allow the virus to access its cellular targets.</jats:p>", "article-number": "vlaf056", "author": [ { "ORCID": "https://orcid.org/0000-0002-2276-0321", "affiliation": [ { "name": "Department of Cellular and Molecular Medicine, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] }, { "name": "Asthma and Airway Disease Research Center, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] }, { "name": "The BIO5 Institute, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] } ], "authenticated-orcid": false, "family": "Pivniouk", "given": "Vadim", "sequence": "first" }, { "affiliation": [ { "name": "Asthma and Airway Disease Research Center, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] } ], "family": "Pivniouk", "given": "Oksana", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Immunobiology, The University of Arizona College of Medicine , Tucson, AZ 85724,", "place": [ "United States" ] } ], "family": "Uhrlaub", "given": "Jennifer L", "sequence": "additional" }, { "affiliation": [ { "name": "Asthma and Airway Disease Research Center, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] } ], "family": "Hahn", "given": "Seongmin", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, NY 10029,", "place": [ "United States" ] } ], "family": "Molzahn", "given": "Allyson", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, NY 10029,", "place": [ "United States" ] } ], "family": "Kimura", "given": "Hiroki", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-6310-6801", "affiliation": [ { "name": "Department of Medicine, National Jewish Health , Denver, CO 80206,", "place": [ "United States" ] } ], "authenticated-orcid": false, "family": "Numata", "given": "Mari", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medicine, National Jewish Health , Denver, CO 80206,", "place": [ "United States" ] } ], "family": "Chu", "given": "Hong Wei", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Cellular and Molecular Medicine, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] }, { "name": "Asthma and Airway Disease Research Center, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] }, { "name": "The BIO5 Institute, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] } ], "family": "Ledford", "given": "Julie G", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, NY 10029,", "place": [ "United States" ] } ], "family": "Kraft", "given": "Monica", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-5830-5323", "affiliation": [ { "name": "The BIO5 Institute, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] }, { "name": "Department of Immunobiology, The University of Arizona College of Medicine , Tucson, AZ 85724,", "place": [ "United States" ] }, { "name": "Arizona Center for Aging, University of Arizona College of Medicine , Tucson, AZ 85724,", "place": [ "United States" ] } ], "authenticated-orcid": false, "family": "Nikolich", "given": "Janko Ž", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-5276-8976", "affiliation": [ { "name": "Department of Cellular and Molecular Medicine, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] }, { "name": "Asthma and Airway Disease Research Center, The University of Arizona , Tucson, AZ 85721,", "place": [ "United States" ] }, { 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