Innate Immune Regulation of Zika Virus Infection

项目概要/摘要 寨卡病毒（ZIKV）是一种黄病毒，最近从乌干达出现，进入亚洲，跨越太平洋，现在 进入美洲。ZIKV感染通过受感染蚊子的叮咬传播给人类。人与人 ZIKV的性传播也有记录。ZIKV感染对未出生儿童构成重大威胁 因为它有效地穿过胎盘屏障以介导子宫内的母体至胎儿传播。胎儿 感染可导致多种病理，包括小头畸形和胎儿死亡。我们对胎盘是如何 细胞响应感染以控制ZIKV嗜性并建立先天免疫防御以保护免受ZIKV 传播和胎儿感染。我们的初步研究表明，ZIKV触发胎盘先天免疫激活， 通过RIG-I感测病毒病原体相关分子模式（PAMPS），但它指导广泛的 阻断细胞因子信号传导，通过信号转导和转录激活因子（STAT）蛋白， 感染细胞这种广泛的STAT抑制减弱干扰素（IFN）先天免疫防御，以支持病毒 复制并传播给胎儿。本提案将调查的中心假设， ZIKV感染和疾病与先天免疫防御的调节和JAK-STAT的控制有关 ZIKV是一种重要的病毒信号传导途径，并且病毒逃避宿主防御使得母胎ZIKV传播和胎儿疾病成为可能。 我们将进行三个目的：1）确定ZIKV诱导先天免疫的分子机制， 整个人类妊娠期间母胎界面关键细胞类型的反应; 2）确定 ZIKV广泛的JAK-STAT调节的分子机制，以及3）定义先天免疫调节的作用。 激活和STAT调节抗病毒防御以控制离体人胎盘细胞的ZIKV感染， 并确定病毒先天免疫逃避如何影响母/胎STAT 2-KI模型中的胎儿疾病 传输

PROJECT SUMMARY/ABSTRACT Zika virus (ZIKV) is a flavivirus that has recently emerged from Uganda, into Asia, across the Pacific and now into the Americas. ZIKV infection is transmitted to humans by the bite of an infected mosquito. Person to person sexual transmission of ZIKV has also been documented. ZIKV infection poses a major threat to unborn children because it efficiently crosses the placental barrier to mediate maternal to fetal transmission in utero. Fetal infection can lead to varied pathologies including microcephaly and fetal death. Little is known of how placental cells respond to infection to control ZIKV tropism and to mount innate immune defenses to protect against ZIKV spread and fetal infection. Our preliminary studies show that ZIKV triggers placental innate immune activation through RIG-I sensing of viral pathogen associated molecular patterns (PAMPS) but that it directs a broad blockade to cytokine signaling through signal transducer and activator of transcription (STAT) proteins in the infected cell. This broad STAT suppression attenuates interferon (IFN) innate immune defenses to support virus replication and spread to the fetus. This proposal will investigate the central hypotheses that the outcome of ZIKV infection and disease is linked with regulation of innate immune defenses and control of JAK-STAT signaling, and that viral evasion of host defenses enables maternal-fetal ZIKV transmission and fetal disease. We will conduct three Aims: 1) Determine the molecular mechanisms by which ZIKV induces innate immune responses in key cell types of the maternal-fetal interface throughout human pregnancy; 2) Determine the molecular mechanisms of broad JAK-STAT regulation by ZIKV, and 3) Define the role of innate immune activation and STAT regulation of antiviral defenses to control ZIKV infection of human placental cells ex vivo, and determine how viral innate immune evasion impacts fetal disease in the STAT2-KI model of maternal/fetal transmission.