Mechanisms of sexual Zika virus transmission and early immunopathogenesis

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ABSTRACT In the past year Zika virus has been rapidly spreading across the globe, compelling the World Health Organization to declare it a global health emergency. Of primary concern is infection in pregnant women, where Zika has been linked to the devastating birth defect microcephaly. While most cases of Zika are likely acquired via mosquito bites, sexual transmission is an increasingly recognized mode of infection. Zika virus remains present in semen even after the resolution of symptoms and detectable viremia in the blood, though it's unclear how long men remain infectious. This puts individuals outside the range of the transmitting mosquito at risk of Zika infection and has prompted public health experts to encourage safe sex as a method of prevention. Here, we propose to study sexual transmission of Zika, taking advantage of an ex-vivo vaginal model of viral infection established by our group. We will use vaginal tissue and primary vaginal epithelial cells to study which cells in the mucosa are initially infected, how quickly the virus replicates, whether migrating cells spread Zika systemically, and how the host responds to infection. Since sexually acquired Zika virus is transmitted in the presence of semen, we will also investigate whether components of semen impact infection. We have found that extracellular vesicles from semen (SEV) readily enter antigen-presenting cells likely to be susceptible to Zika infection, and express receptors known to bind the virus. We have also found that SEV also suppress antigen-specific immunity, likely via impairing antigen-presenting cell function. Thus, we hypothesize that SEV or cell-free seminal plasma will enhance ZIKA infection, either directly, by facilitating viral entry, or indirectly, by compromising immune responses. These studies will inform our understanding of the basic biology of Zika in a biologically relevant model. They will also clarify how semen, a complex and immunologically active carrier of virus, contributes to infection risk for sexually transmitted diseases including Zika.