JAK-STAT Control of Zika Virus-Induced Fetal Injury

JAK-STAT 控制寨卡病毒引起的胎儿损伤

• 批准号: 10441333
• 负责人: KRISTINA M. ADAMS WALDORF
• 金额: $ 84.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441333
• 关键词: Acute; Americas; Anatomy; Animal Model; Animals; Antiviral Agents; Applications Grants; Area; Astrocytes; Binding; Brain; Cell Nucleus; Cell physiology; Cells; Client; Complex; Culicidae; Cytokine Signaling; Data; Data Set; Development; Developmental Gene; Disease; Disease Outbreaks; Epidemic; Epithelial; Eye Injuries; Fetal Development; Fetal Tissues; Flavivirus; Foundations; Gene Expression Profile; Goals; Heat-Shock Proteins 90; Hippocampus (Brain); Human; Human Bites; Immune; Immune response; In Vitro; Infection; Infectious Pregnancy Complications; Injury; Interferons; Investigation; Link; Location; Macaca nemestrina; Maternal-Fetal Transmission; Mediating; Microcephaly; Modeling; Molecular; Mus; Myelogenous; Neurons; Outcome; Output; Pathogenesis; Pathway interactions; Pattern; Phenotype; Phosphotransferases; Placenta; Pregnancy; Process; Proteins; RNA; Regulation; Reporting; Risk; Role; STAT protein; Second Pregnancy Trimester; Sexual Transmission; Signal Transduction; Specificity; Split-Pool Ligation Transcriptome sequencing; Study models; Syndrome; Teratogens; Testing; Therapeutic; Tissues; Translations; Tropism; Vertical Disease Transmission; Viral; Viral Nonstructural Proteins; Viral Pathogenesis; Virus; Work; ZIKV disease; ZIKV infection; Zika Virus; attenuation; base; cell injury; clinically relevant; cytokine; efficacy evaluation; experimental study; fetal; fetal brain injury; gene network; in vivo; lateral ventricle; mouse model; nerve stem cell; neurodevelopment; neurotropic; nonhuman primate; novel; novel therapeutics; novel vaccines; placental infection; pregnant; prevent; public health emergency; trafficking; transcriptome; transcriptomics; trophoblast; vaccine efficacy; viral transmission; virus host interaction

PROJECT SUMMARY/ABSTRACT The recent epidemic of Zika virus (ZIKV) in the Americas was deemed a global public health emergency after an unexpected surge in congenital microcephaly cases suggested that the virus was teratogenic in pregnancy. ZIKV is a flavivirus, primarily transmitted to humans by the bite of infected mosquitoes. ZIKV can infect a variety of placental cells and is also highly neurotropic to target neural progenitor cells, astrocytes and neurons in all stages of development. The congenital ZIKV syndrome describes a severe pattern of placental and fetal brain injury associated with pregnancy infection including microcephaly, ventriculomegaly, and ocular injury. Although the epidemic is now in decline, outbreaks will recur and the US remains at risk for an epidemic. Thus, an enduring need remains to define the viral-host interactions that support ZIKV infection, replication, and maternal-fetal transmission, and to develop a clinically relevant animal model for studies of pathogenesis. Relevant animal models are essential to define the outcome of viral-host interaction within the progression of ZIKV infection and to evaluate the efficacy of vaccines and therapeutics to control ZIKV infection and emergence. We have developed a highly relevant nonhuman primate model of the congenital ZIKV syndrome (Macaca nemestrina, pigtail macaque) in addition to clinically relevant in vitro and ex vivo models of placental and neural stem cell infection. We have shown that ZIKV (1) mediates a broad blockade to the JAK-STAT pathway in infected cells to abrogate cytokine signaling mediated by STATs 1-6, to suppress interferon antiviral defenses; (2) infects trophoblast, myeloid, epithelial, and neural progenitor cells to impose a JAK-STAT blockade through the actions of viral nonstructural protein(s); (3) infects a variety of maternal and fetal tissues in our nonhuman primate model including the neural progenitor cells in the developing fetal brain, and (4) infection reprograms the STAT-dependent fetal brain transcriptome in vivo to alter developmental gene networks. In this resubmission, we present new preliminary data to reveal that ZIKV NS5 binding to HSP90 disrupts the essential interaction of Jak and Tyk2 kinases with HSP90 that otherwise promotes kinase folding and function. The ZIKV NS5-HSP90 interaction suppresses JAK-STAT signaling to abrogate interferon antiviral defenses, which also presents a blockade to cytokine-directed cell-fate decisions signaled via the JAK-STAT pathway that, in part, underlie ZIKV disease. Our central hypothesis is that acute ZIKV infection induces a broad blockade of JAK-STAT signaling involving multiple STATs to suppress antiviral defenses, which enhances vertical transmission and alters fetal brain development. In Aim 1, we will determine how ZIKV mediates a broad JAK-STAT signaling suppression (STAT 1-6) in vitro and ex vivo to control innate immune defenses, viral trafficking and injury. A new feature of Aim 1 is that we will define the outcome of ZIKV NS5 binding to host cell HSP90, which we hypothesize will disrupt client Jak and Tyk2 kinase actions. In Aim 2, we will determine how viral control of JAK-STAT impacts vertical transmission and pathogenesis of fetal brain injury in vivo in a nonhuman primate model of the congenital ZIKV syndrome.

项目总结/摘要 寨卡病毒（ZIKV）最近在美洲的流行被认为是全球公共卫生紧急事件， 先天性小头症个案意外激增，显示该病毒在怀孕期间可引致畸胎。ZIKV是 一种黄病毒，主要通过受感染的蚊子叮咬传播给人类。ZIKV可感染多种胎盘 细胞，并且还高度嗜神经性地靶向神经祖细胞、星形胶质细胞和神经元的所有阶段。 发展先天性ZIKV综合征是一种严重的胎盘和胎儿脑损伤 与妊娠感染相关，包括小头畸形、脑室扩大和眼损伤。虽然 疫情目前正在下降，疫情将再次爆发，美国仍有疫情风险。因此， 仍然需要定义支持ZIKV感染、复制和母胎传播的病毒-宿主相互作用， 并建立临床相关的动物模型用于发病机制的研究。相关动物模型必不可少 定义ZIKV感染进展中病毒-宿主相互作用的结果，并评估ZIKV感染的疗效。 疫苗和治疗剂来控制ZIKV感染和出现。我们开发了一个高度相关的 先天性ZIKV综合征的非人灵长类动物模型（Macaca nemestrina，猪尾猕猴）， 胎盘和神经干细胞感染的临床相关体外和离体模型。我们已经证明ZIKV (1)介导对感染细胞中JAK-STAT途径的广泛阻断，以消除细胞因子介导的信号传导。 通过STATs 1-6，抑制干扰素抗病毒防御;（2）感染滋养层、骨髓、上皮和神经细胞 通过病毒非结构蛋白的作用施加JAK-STAT阻断;（3）感染前体细胞， 在我们的非人灵长类动物模型中的各种母体和胎儿组织中，包括神经前体细胞， （4）感染在体内重编程STAT依赖性胎脑转录组， 发育基因网络在这次重新提交中，我们提出了新的初步数据，以揭示ZIKV NS 5 与HSP 90的结合破坏了Jak和Tyk 2激酶与HSP 90的基本相互作用，否则Jak和Tyk 2激酶会促进HSP 90的表达。 激酶折叠和功能。ZIKV NS 5-HSP 90相互作用抑制JAK-STAT信号传导以消除 干扰素抗病毒防御，这也提出了一个封锁，以尼古丁为导向的细胞命运的决定，通过信号 JAK-STAT途径，部分是ZIKV疾病的基础。我们的中心假设是急性ZIKV感染 诱导涉及多个STAT的JAK-STAT信号传导的广泛阻断以抑制抗病毒防御， 从而增强垂直传播并改变胎儿大脑发育。在目标1中，我们将确定如何 ZIKV在体外和离体介导广泛的JAK-STAT信号传导抑制（STAT 1-6）以控制先天免疫 防御、病毒贩运和伤害。目标1的一个新特征是我们将定义ZIKV NS 5结合的结果 宿主细胞HSP 90，我们假设这将破坏客户端Jak和Tyk 2激酶的行动。在目标2中，我们将确定 JAK-STAT的病毒控制如何影响体内胎儿脑损伤的垂直传播和发病机制， 先天性ZIKV综合征的非人灵长类动物模型。