{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:53:44Z","timestamp":1790679224124,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011446","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T00:00:00Z","timestamp":1696291200000}}],"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T00:00:00Z","timestamp":1695254400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["NeuroZika (ANR-20-CE16-0017)"],"award-info":[{"award-number":["NeuroZika (ANR-20-CE16-0017)"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-10-LABX-62-IBEID"],"award-info":[{"award-number":["ANR-10-LABX-62-IBEID"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-10-LABX-62-IBEID"],"award-info":[{"award-number":["ANR-10-LABX-62-IBEID"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-10-LABX-62-IBEID"],"award-info":[{"award-number":["ANR-10-LABX-62-IBEID"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Zika virus (ZIKV) is a Flavivirus responsible for recent epidemics in Pacific Islands and in the Americas. In humans, the consequences of ZIKV infection range from asymptomatic infection to severe neurological disease such as Guillain-Barr\u00e9 syndrome or fetal neurodevelopmental defects, suggesting, among other factors, the influence of host genetic variants. We previously reported similar diverse outcomes of ZIKV infection in mice of the Collaborative Cross (CC), a collection of inbred strains with large genetic diversity. CC071\/TauUnc (CC071) was the most susceptible CC strain with severe symptoms and lethality. Notably, CC071 has been recently reported to be also susceptible to other flaviviruses including dengue virus, Powassan virus, West Nile virus, and to Rift Valley fever virus. To identify the genetic origin of this broad susceptibility, we investigated ZIKV replication in mouse embryonic fibroblasts (MEFs) from CC071 and two resistant strains. CC071 showed uncontrolled ZIKV replication associated with delayed induction of type-I interferons (IFN-I). Genetic analysis identified a mutation in the <jats:italic>Irf3<\/jats:italic> gene specific to the CC071 strain which prevents the protein phosphorylation required to activate interferon beta transcription. We demonstrated that this mutation induces the same defective IFN-I response and uncontrolled viral replication in MEFs as an <jats:italic>Irf3<\/jats:italic> knock-out allele. By contrast, we also showed that <jats:italic>Irf3<\/jats:italic> deficiency did not induce the high plasma viral load and clinical severity observed in CC071 mice and that susceptibility alleles at other genes, not associated with the IFN-I response, are required. Our results provide new insight into the <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> roles of <jats:italic>Irf3<\/jats:italic>, and into the genetic complexity of host responses to flaviviruses.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011446","type":"journal-article","created":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T17:49:32Z","timestamp":1695318572000},"page":"e1011446","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in 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