Mechanisms of Zika Virus Maternal-Fetal Transmission

项目摘要： 寨卡病毒（ZIKV）是一种新出现的蚊媒黄病毒，已成为全球公共卫生威胁。 ZIKV感染现在已经与成人格林-巴利综合征和小头畸形的病例有因果关系， 胎儿宫内生长受限（IUGR）和自然流产的母亲感染的背景下， 怀孕鉴于对这种因果关系的认识，必须确定 母婴传播深入了解这些机制可以提高我们减轻负担的能力， 寨卡病毒感染对孕妇的影响这个合作和互动项目的目标是 定义宿主防御反应如何控制或可能有助于ZIKV发病过程中和之后 怀孕前提是基于广泛的新发表的数据，这些数据显示ZIKV感染 怀孕小鼠导致胎盘感染、宫内传播和对发育中的胎儿的损伤。O ur 核心假设是， 母胎传播的发生是因为ZIKV克服了胎盘滋养层细胞 宿主防御（自噬）（目的1），篡夺TAM受体进入胎盘滋养层和内皮细胞 (Aim 2）;并且这一整个过程在具有足够免疫力的黄病毒免疫个体或动物中增强。 促进ADE的交叉反应性、非中和性抗ZIKV抗体的水平（目的3）。总体而言，我们 这些努力对于理解ZIKV的发病机制将是非常重要的。这项工作将提供一个基础， 确定ZIKV母婴传播风险的临床研究，产生了可能的新的 治疗方法，并确定ZIKV和其他天然免疫之间的相互作用， 黄病毒

Project Summary: Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that has become a global public health threat. ZIKV infection has now been causally linked to cases of Guillain-Barre syndrome in adults and microcephaly, intrauterine growth restriction (IUGR), and spontaneous abortion in the setting of maternal infection during pregnancy. Given the recognition of this causal relationship, it is imperative to determine the mechanism(s) of maternal-fetal transmission. Insights into such mechanisms could improve our ability to reduce the burden of the effects of Zika virus infection during pregnancy. The goal of this collaborative and interactive project is to define how host defense responses can control or possibly contribute to ZIKV pathogenesis during and after pregnancy. The premise is based on the extensive newly published data showing that ZIKV infection of pregnant mice results in infection of the placenta, in utero transmission, and injury to the developing fetus. O ur central hypotheses are that maternal-fetal transmission occurs because ZIKV overcomes placental trophoblast host defenses (autophagy) (Aim 1), usurps TAM receptors to enter placental trophoblasts and endothelial cells (Aim 2); and this entire process is enhanced in flavivirus-immune individuals or animals who have sufficient levels of cross-reactive, non-neutralizing anti-ZIKV antibodies that promote ADE (Aim 3). Collectively, our efforts will be highly significant for understanding ZIKV pathogenesis. This work will provide a foundation for clinical studies that define the risks of maternal to child transmission of ZIKV, generate possible new therapeutic approaches, and determine the interaction between ZIKV and natural immunity to other flaviviruses.