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Innate Immune Regulation of Zika Virus Infection

寨卡病毒感染的先天免疫调节

基本信息

批准号：
10582620
负责人：
Carolyn B Coyne
金额：
$ 78.73万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582620
关键词：
Affect Africa Alanine Americas Amino Acids Asia Attenuated Binding Biological Models Brain Injuries Brazil Cell Separation Cells Complement Congenital Abnormality Culicidae Cytokine Signaling Data Decidua Diamond Disease Epidemic Equilibrium Fetal Death Fetal Diseases Fetal Growth Retardation Fetus Fever Flavivirus Gestational Age Goals Grant Heat-Shock Proteins 90 Host Defense Human Human Bites IFNAR1 gene Immune Immune Evasion Immune response Immune signaling Immunocompetent Infection Injury Innate Immune Response Interferon Type I Interferons Laboratories Link Maternal-Fetal Exchange Maternal-Fetal Transmission Mediating Microcephaly Micronesia Modeling Molecular Molecular Chaperones Mothers Mus Mutagenesis Mutation Analysis Nature Organoids Outcome Pathogenesis Pathology Pathway interactions Pattern Persons Phenotype Physiological Placenta Positioning Attribute Pregnancy Pregnant Women Process Proteins Public Health Regulation Role STAT protein STAT1 gene STAT1 protein STAT2 gene Scanning Sexual transmission of Zika Signal Pathway Signal Transduction Spontaneous abortion Structure Transcriptional Regulation Transgenic Model Tropism Uganda Vertical Transmission Viral Virus Virus Diseases Virus Replication ZIKV disease ZIKV infection Zika Virus antiviral immunity cell type design disease transmission domain mapping experimental study fetal fetal infection functional outcomes genetic approach human tissue immune activation immunoregulation in utero in vivo Model innovation microbial mouse model novel pathogenic virus response transmission process trophoblast unborn child vascular injury virus host interaction

项目摘要

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.

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。