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In this study, using lymphocytic choriomeningitis virus (LCMV) and Zika virus (ZIKV) in wild-type mice, we show that these viruses replicate in the vaginal mucosa with minimal induction of antiviral interferon and inflammatory response, causing dampened innate-mediated control of viral replication and a failure to mature local antigen-presenting cells (APCs). Enhancement of innate-mediated inflammation in the vaginal mucosa rescues this phenotype and completely inhibits ZIKV replication. To gain a better understanding of how this dampened innate immune activation in the lower female reproductive tract may also affect adaptive immunity, we modeled CD8 T cell responses using vaginal LCMV infection. We show that the lack of APC maturation in the vaginal mucosa leads to a delay in CD8 T cell activation in the draining lymph node and hinders the timely appearance of effector CD8 T cells in vaginal mucosa, thus further delaying viral control in this tissue. Our study demonstrates that vaginal tissue is exceptionally vulnerable to infection by RNA viruses and provides a conceptual framework for the male to female sexual transmission observed during ZIKV infection.<\/jats:p>","DOI":"10.1084\/jem.20161289","type":"journal-article","created":{"date-parts":[[2016,11,16]],"date-time":"2016-11-16T10:14:48Z","timestamp":1479291288000},"page":"2913-2929","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":45,"title":["Dampened antiviral immunity to intravaginal exposure to RNA viral pathogens allows enhanced viral replication"],"prefix":"10.1084","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2975-6621","authenticated-orcid":false,"given":"Shahzada","family":"Khan","sequence":"first","affiliation":[{"name":"Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik M.","family":"Woodruff","sequence":"additional","affiliation":[{"name":"Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Trapecar","sequence":"additional","affiliation":[{"name":"Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krystal A.","family":"Fontaine","sequence":"additional","affiliation":[{"name":"Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Ezaki","sequence":"additional","affiliation":[{"name":"Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7638-6382","authenticated-orcid":false,"given":"Timothy C.","family":"Borbet","sequence":"additional","affiliation":[{"name":"Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Ott","sequence":"additional","affiliation":[{"name":"Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158 1"},{"name":"Department of Medicine, University of California, San Francisco, San Francisco, CA 94143 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3097-9665","authenticated-orcid":false,"given":"Shomyseh","family":"Sanjabi","sequence":"additional","affiliation":[{"name":"Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158 1"},{"name":"Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,11,16]]},"reference":[{"key":"2023072603220665300_bib1","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1086\/425079","article-title":"Toll-like receptor (TLR)-3, but not TLR4, agonist protects against genital herpes infection in the absence of inflammation seen with CpG DNA","volume":"190","author":"Ashkar","year":"2004","journal-title":"J. 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