Mechanisms of sexual Zika virus transmission and early immunopathogenesis

摘要 在过去的一年里，寨卡病毒在地球仪迅速蔓延，迫使世界卫生组织 该组织宣布这是一个全球卫生紧急情况。主要关注的是孕妇的感染， 寨卡病毒与毁灭性的出生缺陷小头畸形症有关。虽然大多数寨卡病例都是 性传播很可能是通过蚊虫叮咬获得的，是一种越来越被认识到的感染方式。 寨卡病毒仍然存在于精液中，即使在症状消退和可检测到的病毒血症之后， 血液，虽然目前还不清楚多久男性仍然具有传染性。这使得个人超出了 传播蚊子的寨卡病毒感染的风险，并促使公共卫生专家鼓励安全 性作为一种预防手段。在这里，我们建议研究寨卡病毒的性传播，利用 我们小组建立的离体阴道病毒感染模型。我们将使用阴道组织， 原代阴道上皮细胞，以研究粘膜中的哪些细胞最初被感染， 病毒复制，迁移细胞是否会全身传播寨卡病毒，以及宿主如何对感染做出反应。 由于性获得性寨卡病毒是在精液存在的情况下传播的，我们也将进行调查 精液成分是否影响感染。我们发现精液中的细胞外囊泡 (SEV)很容易进入可能对寨卡病毒感染易感的抗原呈递细胞，并表达 已知能与病毒结合的受体我们还发现SEV还抑制抗原特异性免疫， 很可能是通过损害抗原呈递细胞的功能因此，我们假设SEV或无细胞精液 血浆将通过促进病毒进入而直接增强ZIKA感染，或者通过促进病毒进入而间接增强ZIKA感染。 危及免疫反应这些研究将使我们了解 寨卡病毒在生物学相关模型中。他们还将阐明精液，一个复杂的和免疫学上 病毒的活跃携带者，增加了包括寨卡病毒在内的性传播疾病的感染风险。

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.