Innate Immune Regulation of Zika Virus Infection

项目摘要/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，横跨太平洋，现在 进入美洲。寨卡病毒感染是通过受感染蚊子的叮咬传播给人类的。人对人 ZIKV的性传播也被记录在案。寨卡病毒感染对未出生的儿童构成重大威胁 因为它能有效地穿过胎盘屏障，在子宫内介导母婴传播。胎儿 感染可导致多种病理，包括小头畸形和胎儿死亡。很少有人知道胎盘是如何形成的 细胞对感染作出反应以控制ZIKV的嗜性并建立天然免疫防御系统以保护ZIKV 传播和胎儿感染。我们的初步研究表明，ZIKV可触发胎盘先天免疫激活 通过RIG-I检测病毒病原体相关分子模式(PAMPS)，但它指向广泛的 通过信号转导和转录激活子蛋白阻断细胞因子信号转导 被感染的细胞。这种广泛的STAT抑制减弱了干扰素(干扰素)支持病毒的天然免疫防御 复制并传播到胎儿。这项提案将调查以下核心假设： ZIKV感染和疾病与天然免疫防御的调节和JAK状态的控制有关 信号，病毒逃避宿主防御，导致母婴ZIKV传播和胎儿疾病。 我们将进行三个目标：1)确定ZIKV诱导天然免疫的分子机制 人妊娠期间母胎界面关键细胞类型的反应；2)决定 ZIKV广泛的JAK-STAT调节的分子机制，以及3)天然免疫的作用 抗病毒防御系统在体外控制人胎盘细胞ZIKV感染的激活和状态调节， 并在母亲/胎儿的STAT2-KI模型中确定病毒先天免疫逃避如何影响胎儿疾病 变速箱。

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.