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Despite over one hundred years of research on these viruses, the underpinnings of the molecular mechanisms driving virally induced damage to the CNS remain unresolved. Moreover, virally induced encephalitis following exposure to these viruses causes catastrophic damage to the CNS, and survivors of infection often suffer from permanent neurological sequelae as a result of sustained neuroinflammation and neurological insults encountered. Animal models are undoubtedly invaluable tools in biomedical research, where physiologically relevant models are required to study pathogenesis and host\u2013pathogen interactions. Here, we review the literature to examine nonhuman primate (NHP) and mouse models of infection for EEEV, VEEV, and WEEV. We provide a brief overview of relevant background information for each virus, including geography, epidemiology, and clinical disease. The primary focus of this review is to describe neuropathological features associated with CNS disease in NHP and mouse models of infection and compare CNS invasion and neuropathogenesis for aerosol, intranasal, and subcutaneous routes of exposure to EEEV, VEEV, and WEEV.<\/jats:p>","DOI":"10.3390\/pathogens14020193","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T11:14:41Z","timestamp":1739531681000},"page":"193","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Neuropathogenesis of Encephalitic Alphaviruses in Non-Human Primate and Mouse Models of Infection"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8012-5377","authenticated-orcid":false,"given":"Caitlin M.","family":"Woodson","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA"},{"name":"Center for Emerging, Zoonotic, and Arthropod-Borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon K.","family":"Carney","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA"},{"name":"Center for Emerging, Zoonotic, and Arthropod-Borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8036-7213","authenticated-orcid":false,"given":"Kylene","family":"Kehn-Hall","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA"},{"name":"Center for Emerging, Zoonotic, and Arthropod-Borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ronca, S.E., Dineley, K.T., and Paessler, S. 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