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New approaches are needed to understand enteric pathogenesis and to develop vaccines and therapeutics to prevent the spread of these viruses. Here, we exploited a reverse genetic system for an enteric CoV, porcine epidemic diarrhea virus (PEDV), and outline an approach of genetically inactivating highly conserved viral factors known to limit the host innate immune response to infection. Our report reveals that generating PEDV with inactive versions of three viral interferon antagonists, nonstructural proteins 1, 15, and 16, results in a highly attenuated virus that does not cause diarrhea in animals and elicits a neutralizing antibody response in virus-infected animals. This strategy may be useful for generating live attenuated vaccine candidates that prevent disease and fecal spread of enteric CoVs, including SARS-CoV-2.<\/jats:p>","DOI":"10.1128\/jvi.00565-20","type":"journal-article","created":{"date-parts":[[2020,6,17]],"date-time":"2020-06-17T13:17:42Z","timestamp":1592399862000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":39,"title":["Inactivating Three Interferon Antagonists Attenuates Pathogenesis of an Enteric Coronavirus"],"prefix":"10.1128","volume":"94","author":[{"given":"Xufang","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra C.","family":"Buckley","sequence":"additional","affiliation":[{"name":"Virus and Prion Research Unit, USDA-ARS-National Animal Disease 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