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: 10668233
• 负责人: KRISTINA M. ADAMS WALDORF
• 金额: $ 80.8万
• 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/10668233
• 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; Eye Injuries; Fetal Development; Fetal Tissues; Flavivirus; Foundations; Gene Expression Profile; Goals; Heat-Shock Proteins 90; Hippocampus; 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; Myeloid Progenitor Cells; Neurons; Outcome; Output; Pathogenesis; Pathway interactions; Pattern; Phenotype; Phosphotransferases; Physiology; Placenta; Pregnancy; Process; Proteins; RNA; Recurrence; Regulation; Reporting; 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 Transmission; Viral; Viral Nonstructural Proteins; Viral Pathogenesis; Virus; Work; ZIKV disease; ZIKV infection; Zika Virus; attenuation; cell injury; clinically relevant; cytokine; efficacy evaluation; epidemic potential; epithelial stem cell; 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; placental stem cell; pregnant; prevent; programs; public health emergency; trafficking; transcriptome; transcriptomics; transmission process; trophoblast stem cell; vaccine efficacy; 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.

项目摘要/摘要 最近在美洲流行的寨卡病毒(ZIKV)被认为是全球突发公共卫生事件，此前 先天性小头畸形病例的意外激增表明，该病毒在怀孕期间具有致畸性。ZIKV是 一种黄病毒，主要通过受感染的蚊子的叮咬传播给人类。ZIKV可感染多种胎盘 细胞，对神经前体细胞、星形胶质细胞和神经元具有高度的神经亲和性。 发展。先天性ZIKV综合征描述了一种严重的胎盘和胎儿脑损伤模式 与妊娠感染有关，包括小头畸形、脑室肥大和眼部损伤。尽管 疫情现在正在下降，疫情将再次爆发，美国仍有爆发疫情的风险。因此，一种持久的需求 仍有待定义支持ZIKV感染、复制和母婴传播的病毒-宿主相互作用， 并为发病机制的研究建立具有临床意义的动物模型。相关的动物模型必不可少 明确ZIKV感染进展过程中病毒-宿主相互作用的结果，并评估其疗效 使用疫苗和治疗药物来控制寨卡病毒的感染和出现。我们已经开发出一种高度相关的 先天性ZIKV综合征(恒河猴、辫尾猕猴)的非人灵长类模型 临床相关的胎盘和神经干细胞感染的体外和体外模型。我们已经证明了ZIKV (1)在感染细胞中广泛阻断JAK-STAT通路，以消除细胞因子介导的信号转导 通过STAT1-6抑制干扰素抗病毒防御；(2)感染滋养层细胞、髓样细胞、上皮细胞和神经 祖细胞通过病毒非结构蛋白的作用施加JAK-STAT阻断(S)；(3)感染 在我们的非人灵长类动物模型中母体和胎儿组织的多样性，包括 发育中的胎儿大脑，以及(4)感染在体内重新编程依赖于STAT的胎儿大脑转录组以改变 发育基因网络。在这次重新提交中，我们提供了新的初步数据来揭示ZIKV NS5 与HSP90的结合破坏了JAK和TYK2激酶与HSP90的基本相互作用，否则HSP90会促进 蛋白激酶的折叠和功能。ZIKV NS5-HSP90相互作用抑制JAK-STAT信号转导 干扰素抗病毒防御，这也是对细胞因子指示的细胞命运决定的阻断，通过 JAK-STAT途径，部分是ZIKV疾病的基础。我们的中心假设是急性寨卡病毒感染 诱导涉及多个STATs的JAK-STAT信号的广泛阻断，以抑制抗病毒防御， 这会增强垂直传播并改变胎儿大脑的发育。在目标1中，我们将确定如何 ZIKV在体外和体外介导广泛的JAK-STAT信号抑制(STAT1-6)以控制先天性免疫 防御、病毒贩运和伤害。目标1的一个新特性是，我们将定义ZIKV NS5绑定的结果 宿主细胞HSP90，我们假设这将扰乱客户端JAK和TYK2激酶的作用。在目标2中，我们将确定 JAK-STAT的病毒控制如何影响体内垂直传播和胎脑损伤的发病机制 先天性ZIKV综合征的非人灵长类动物模型。

项目成果

Type I Interferon Orchestrates Demand-Adapted Monopoiesis during Influenza A Virus Infection via STAT1-Mediated Upregulation of Macrophage Colony-Stimulating Factor Receptor Expression.

I 型干扰素在甲型流感病毒感染期间通过 STAT1 介导的巨噬细胞集落刺激因子受体表达上调来协调需求适应的单核细胞生成。

• DOI: 10.1128/jvi.00102-23
• 发表时间: 2023
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Lin,Sue-Jane;Lin,Kai-Min;Chen,Shi-YoJill;Ku,Chia-Chi;Huang,Chen-Wei;Huang,Chi-Hsiang;GaleJr,Michael;Tsai,Ching-Hwa
• 通讯作者: Tsai,Ching-Hwa