{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:04:29Z","timestamp":1790949869138,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010384","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T00:00:00Z","timestamp":1647388800000}}],"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T00:00:00Z","timestamp":1646352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1ZIAAI001102"],"award-info":[{"award-number":["1ZIAAI001102"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>The California serogroup (CSG) of <jats:italic>Orthobunyaviruses<\/jats:italic> comprises several members capable of causing neuroinvasive disease in humans, including <jats:italic>La Crosse orthobunyavirus<\/jats:italic> (LACV), <jats:italic>Jamestown Canyon orthobunyavirus<\/jats:italic> (JCV), and <jats:italic>Inkoo orthobunyavirus<\/jats:italic> (INKV). Despite being genetically and serologically closely related, their disease incidences and pathogenesis in humans and mice differ. We have previously shown that following intraperitoneal inoculation of weanling mice, LACV was highly pathogenic while JCV and INKV were not. To determine why there were differences, we examined the ability of these viruses to invade the CNS and compared the host innate immune responses that regulated viral pathogenesis. We found that LACV was always neuroinvasive, which correlated with its high level of neuroinvasive disease. Interestingly, JCV was not neuroinvasive in any mice, while INKV was neuroinvasive in most mice. The type I interferon (IFN) response was critical for protecting mice from both JCV and INKV disease, although in the periphery JCV induced little IFN expression, while INKV induced high IFN expression. Despite their differing neuroinvasive abilities, JCV and INKV shared innate signaling components required for protection. The presence of either cytoplasmic Rig-I-Like Receptor signaling or endosomal Toll-Like Receptor signaling was sufficient to protect mice from JCV or INKV, however, inhibition of both pathways rendered mice highly susceptible to neurological disease. Comparison of IFN and IFN-stimulated gene (ISG) responses to INKV in the brains of resistant wild type (WT) mice and susceptible immune knockout mice showed similar IFN responses in the brain, but WT mice had higher ISG responses, suggesting induction of key ISGs in the brain is critical for protection of mice from INKV. Overall, these results show that the CSG viruses differ in neuroinvasiveness, which can be independent from their neuropathogenicity. The type I IFN response was crucial for protecting mice from CSG virus-induced neurological disease, however, the exact correlates of protection appear to vary between CSG viruses.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010384","type":"journal-article","created":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T18:41:13Z","timestamp":1646419273000},"page":"e1010384","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Differences in neuroinvasion and protective innate immune pathways between encephalitic California Serogroup orthobunyaviruses"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3766-9272","authenticated-orcid":true,"given":"Alyssa B.","family":"Evans","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clayton W.","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4177-7249","authenticated-orcid":true,"given":"Karin E.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"issue":"9","key":"ppat.1010384.ref001","doi-asserted-by":"crossref","DOI":"10.3390\/v11090794","article-title":"Throw out the Map: Neuropathogenesis of the Globally Expanding California Serogroup of Orthobunyaviruses","volume":"11","author":"AB Evans","year":"2019","journal-title":"Viruses"},{"issue":"7","key":"ppat.1010384.ref002","doi-asserted-by":"crossref","first-page":"e6145","DOI":"10.1371\/journal.pone.0006145","article-title":"The incidence risk, clustering, and clinical presentation of La Crosse virus infections in the eastern United States, 2003\u20132007","volume":"4","author":"AD Haddow","year":"2009","journal-title":"PLoS One"},{"issue":"34","key":"ppat.1010384.ref003","doi-asserted-by":"crossref","first-page":"929","DOI":"10.15585\/mmwr.mm6434a1","article-title":"West Nile Virus and Other Nationally Notifiable Arboviral Diseases\u2014United States, 2014","volume":"64","author":"NP Lindsey","year":"2015","journal-title":"MMWR Morb Mortal Wkly Rep."},{"issue":"6","key":"ppat.1010384.ref004","doi-asserted-by":"crossref","first-page":"117","DOI":"10.14745\/ccdr.v41i06a01","article-title":"Emerging mosquito-borne bunyaviruses in Canada","volume":"41","author":"MA Drebot","year":"2015","journal-title":"Can Commun Dis Rep"},{"key":"ppat.1010384.ref005","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.meegid.2013.09.023","article-title":"The variability of the large genomic segment of Tahyna orthobunyavirus and an all-atom exploration of its anti-viral drug resistance","volume":"20","author":"P Kilian","year":"2013","journal-title":"Infect Genet Evol"},{"issue":"5","key":"ppat.1010384.ref006","doi-asserted-by":"crossref","first-page":"810","DOI":"10.3201\/eid2205.151015","article-title":"Acute Human Inkoo and Chatanga Virus Infections, Finland","volume":"22","author":"N Putkuri","year":"2016","journal-title":"Emerg Infect Dis"},{"issue":"2","key":"ppat.1010384.ref007","doi-asserted-by":"crossref","first-page":"384","DOI":"10.4269\/ajtmh.15-0196","article-title":"2nd, Fischer M, Staples JE. 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