title: Dampened antiviral immunity to intravaginal exposure to RNA viral pathogens allows enhanced viral replication.
abstract: Understanding the host immune response to vaginal exposure to RNA viruses is required to combat sexual transmission of this class of pathogens. 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.
authors.affiliation: Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158.
authors.forename: Shahzada
authors.identifier: 0000-0003-2975-6621
authors.initials: S
authors.lastname: Khan
authors.affiliation: Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Woodruff
authors.affiliation: Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158.
authors.forename: Martin
authors.initials: M
authors.lastname: Trapecar
authors.affiliation: Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158.
authors.forename: Krystal A
authors.initials: KA
authors.lastname: Fontaine
authors.affiliation: Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158.
authors.forename: Ashley
authors.initials: A
authors.lastname: Ezaki
authors.affiliation: Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158.
authors.forename: Timothy C
authors.identifier: 0000-0001-7638-6382
authors.initials: TC
authors.lastname: Borbet
authors.affiliation: Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158.|Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ott
authors.affiliation: Virology and Immunology, Gladstone Institutes, San Francisco, CA 94158 shomyseh.sanjabi@gladstone.ucsf.edu.|Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Shomyseh
authors.identifier: 0000-0002-3097-9665
authors.initials: S
authors.lastname: Sanjabi
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D007113:Immunity, Innate; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D014621:Vagina / Q000276:immunology* / Q000473:pathology / Q000821:virology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*; D000071244:Zika Virus / Q000502:physiology*; D000071243:Zika Virus Infection / Q000235:genetics / Q000276:immunology* / Q000473:pathology