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In humans, RVF spans a variety of clinical manifestations, ranging from an acute flu-like illness to severe forms of disease, including late-onset encephalitis. The large variations in human RVF disease are inadequately represented by current murine models, which overwhelmingly die of early-onset hepatitis. Existing mouse models of RVF encephalitis are either immunosuppressed, display an inconsistent phenotype, or develop encephalitis only when challenged via intranasal or aerosol exposure. In this study, the genetically defined recombinant inbred mouse resource known as the Collaborative Cross (CC) was used to identify mice with additional RVF disease phenotypes when challenged via a peripheral foot-pad route to mimic mosquito-bite exposure. Wild-type Rift Valley fever virus (RVFV) challenge of 20 CC strains revealed three distinct disease phenotypes: early-onset hepatitis, mixed phenotype, and late-onset encephalitis. Strain CC057\/Unc, with the most divergent phenotype, which died of late-onset encephalitis at a median of 11 days post-infection, is the first mouse strain to develop consistent encephalitis following peripheral challenge. CC057\/Unc mice were directly compared to C57BL\/6 mice, which uniformly succumb to hepatitis within 2\u20134 days of infection. Encephalitic disease in CC057\/Unc mice was characterized by high viral RNA loads in brain tissue, accompanied by clearance of viral RNA from the periphery, low ALT levels, lymphopenia, and neutrophilia. In contrast, C57BL\/6 mice succumbed from hepatitis at 3 days post-infection with high viral RNA loads in the liver, viremia, high ALT levels, lymphopenia, and thrombocytopenia. The identification of a strain of CC mice as an RVFV encephalitis model will allow for future investigation into the pathogenesis and treatment of RVF encephalitic disease and indicates that genetic background makes a major contribution to RVF disease variation.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010649","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T17:23:31Z","timestamp":1657819411000},"page":"e1010649","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":44,"title":["Genetic diversity of collaborative cross mice enables identification of novel rift valley fever virus encephalitis model"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7844-4838","authenticated-orcid":true,"given":"Haley N.","family":"Cartwright","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique J.","family":"Barbeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Doyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ed","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Heise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin T.","family":"Ferris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6764-7536","authenticated-orcid":true,"given":"Anita K.","family":"McElroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,7,14]]},"reference":[{"issue":"6","key":"ppat.1010649.ref001","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/0035-9203(79)90006-3","article-title":"Epidemic Rift Valley fever in Egypt: observations of the spectrum of human illness","volume":"73","author":"LW Laughlin","year":"1979","journal-title":"Trans R Soc Trop Med Hyg"},{"issue":"3\u20134","key":"ppat.1010649.ref002","first-page":"183","article-title":"Clinical studies on Rift Valley fever. 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