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Therapeutic effects of the receptor for advanced glycation end products (RAGE) were reported in many inflammatory diseases. However, a therapeutic effect of RAGE in COVID-19 has not been reported. In the present study, we investigated whether and how the RAGE-Ig fusion protein would have an antiviral and anti-inflammatory therapeutic effect in the COVID-19 system. The protective therapeutic effect of RAGE-Ig was determined in vivo in K18-hACE2 transgenic mice and Syrian golden hamsters infected with six VOCs of SARS-CoV-2. The underlying antiviral mechanism of RAGE-Ig was determined in vitro in SARS-CoV-2\u2013infected human lung epithelial cells (BEAS-2B). Following treatment of K18-hACE2 mice and hamsters infected with various SARS-CoV-2 VOCs with RAGE-Ig, we demonstrated (1) significant dose-dependent protection (i.e., greater survival, less weight loss, lower virus replication in the lungs); (2) a reduction of inflammatory macrophages (F4\/80+\/Ly6C+) and neutrophils (CD11b+\/Ly6G+) infiltrating the infected lungs; (3) a RAGE-Ig dose-dependent increase in the expression of type I IFNs (IFN-\u03b1 and IFN-\u03b2) and type III IFN (IFN\u03bb2) and a decrease in the inflammatory cytokines (IL-6 and IL-8) in SARS-CoV-2\u2013infected human lung epithelial cells; and (4) a dose-dependent decrease in the expression of CD64 (FcgR1) on monocytes and lung epithelial cells from symptomatic COVID-19 patients. Our preclinical findings revealed type I and III IFN-mediated antiviral and anti-inflammatory therapeutic effects of RAGE-Ig protein against COVID-19 caused by multiple SARS-CoV-2 VOCs.<\/jats:p>","DOI":"10.4049\/jimmunol.2300392","type":"journal-article","created":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T14:07:35Z","timestamp":1704463655000},"page":"576-585","source":"Crossref","is-referenced-by-count":10,"title":["Antiviral and Anti-Inflammatory Therapeutic Effect of RAGE-Ig Protein against Multiple SARS-CoV-2 Variants of Concern Demonstrated in K18-hACE2 Mouse and Syrian Golden Hamster Models"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8184-4050","authenticated-orcid":false,"given":"Nisha Rajeswari","family":"Dhanushkodi","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3986-890X","authenticated-orcid":false,"given":"Swayam","family":"Prakash","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0212-5854","authenticated-orcid":false,"given":"Afshana","family":"Quadiri","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Latifa","family":"Zayou","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchi","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4563-1749","authenticated-orcid":false,"given":"Amin Mohammed","family":"Shaik","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4447-5385","authenticated-orcid":false,"given":"Berfin","family":"Suzer","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela Coimbra","family":"Ibraim","sequence":"additional","affiliation":[{"name":"High Containment Facility, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Landucci","sequence":"additional","affiliation":[{"name":"High Containment Facility, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia F","family":"Tifrea","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4649-8572","authenticated-orcid":false,"given":"Mahmoud","family":"Singer","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Jamal","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9145-382X","authenticated-orcid":false,"given":"Robert A","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine School of Medicine , Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hawa","family":"Vahed","sequence":"additional","affiliation":[{"name":"Department of Vaccines and Immunotherapies, TechImmune, LLC, University Lab Partners , Irvine, 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Pharmacol."},{"key":"2025020405444070500_r20","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1681\/ASN.2005010062","article-title":"Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy","volume":"16","author":"Forbes","year":"2005","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025020405444070500_r21","doi-asserted-by":"crossref","first-page":"3785","DOI":"10.3390\/jcm9113785","article-title":"Soluble receptor for advanced glycation end products and its forms in COVID-19 patients with and without diabetes mellitus: a pilot study on their role as disease biomarkers","volume":"9","author":"Dozio","year":"2020","journal-title":"J. Clin. 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(Lausanne)"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/212\/4\/576\/61474940\/ji2300392.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/212\/4\/576\/61474940\/ji2300392.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T05:47:03Z","timestamp":1738648023000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/212\/4\/576\/7926075"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,5]]},"references-count":40,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,2,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2300392","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,2]]},"published":{"date-parts":[[2024,1,5]]}}}