Cell Death Pathways in Cytomegalovirus Pathogenesis and Control

巨细胞病毒发病机制和控制中的细胞死亡途径

基本信息

批准号：
8813786
负责人：
EDWARD S. Edward S Mocarski
金额：
$ 38.79万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8813786
关键词：
Address Animals Apoptosis Apoptotic Caspase Cell Death Cell Death Signaling Process Cell Lineage Cells Cessation of life Characteristics Complex Cytomegalovirus Cytomegalovirus Infections DNA Viruses Development Disease Embryo Event Evolution Experimental Animal Model Health Host Defense Human Immune Immune system Immunocompromised Host Infection Infection Control Infection prevention Inflammation Inflammatory Knowledge Link Mammals Mediating Mediator of activation protein Medical Mitochondria Murid herpesvirus 1 Mus Mutant Strains Mice Nature Necrosis Newborn Infant Nuclear Outcome Pathogenesis Pathway interactions Phosphotransferases Play Primates Production Proteins RIPK3 gene Race Regulation Risk Rodent Role Running Signal Pathway Signal Transduction Staging System Systemic infection TLR3 gene TLR4 gene Tissues Viral Virus Virus Diseases arm caspase-8 cost fighting fitness human RIPK3 protein inhibitor/antagonist macrophage monocyte mutant pathogen prevent programs protein protein interaction sensor

项目摘要

DESCRIPTION (provided by applicant): Cell Death Pathways in Cytomegalovirus Pathogenesis and Control Cytomegalovirus (CMV) is a major cause of disease in newborns and immunocompromised hosts. Contributing to medical significance, this virus encodes an arsenal of immunomodulatory gene products that assure efficient systemic infection as well as long-term persistence and latency. This project focuses on host defense at the portal of entry in the first cells that become infected. We address the interplay of host programmed cell death (PCD) pathways and the CMV-encoded suppressors that inhibit cell death in sculpting pathogenesis. Importantly, PCD pathways interface with CMV-encoded suppressors in an evolutionarily conserved fashion such that there are mechanistic similarity in murine and human CMV. Extrinsic apoptosis mediated through caspase 8 and necrosis mediated by receptor interacting protein 3 (RIP3) kinase play out within infected cells by interfacing with two interlocked classes of CMV cell death suppressors, one that is betaherpesvirus- conserved and suppresses caspase 8 activation (vICA) and the other, recently discovered, that blocks necrotic cell death (vIRA) unleashed by vICA inhibition of caspase 8. The necrotic PCD pathway and the relationship between vICA and vIRA were brought to light through our incisive studies employing murine CMV and mutant strains of mice. Here, we will investigate the interplay of these virus-encoded PCD suppressors and the cognate PCD pathways they inhibit, identifying key mechanism(s) that likely have broad significance in pathogen-host interactions. Relevance to human CMV will be established by identifying the RIP3-dependent necrotic death suppressor(s) encoded by this virus and studying mechanism. We will determine the role of apoptosis and necrosis in the earliest stages of infection of monocyte-derived macrophage. In this manner, we gain knowledge and understanding relevant to conserved aspects of apoptotic and necrotic PCD in host defense, which is the only immune mechanism currently able to completely stop virus and prevent infection: Specific Aim 1 will identify the human CMV-encoded inhibitor of RIP3-dependent necrosis and investigate the interplay of inhibitors of extrinsic apoptosis (caspase 8) and necrosis (RIP3) on cell fate outcomes, focusing on changes in protein-protein interactions and cell signaling machinery that trigger cell death. Specific Aim will evaluate the contribution of caspase 8- and RIP3-regulated cell death pathways to cell fate outcome by investigating the mechanism of Casp8 inhibition by vICA, as well as changes in protein-protein interactions that contribute to RIP3 RHIM- and kinase-dependent necrosis in cells and mice.

描述（由申请人提供）：巨细胞病毒发病机理和对照巨细胞病毒（CMV）中的细胞死亡途径是新生儿和免疫功能低下宿主的主要原因。促进医学意义的原因，该病毒编码了免疫调节基因产物的武器，可确保有效的全身感染以及长期持久性和潜伏期。该项目的重点是在被感染的第一个细胞中进入入口门户的宿主防御。我们解决了宿主程序性细胞死亡（PCD）途径的相互作用和CMV编码的抑制器，这些抑制器抑制了雕塑发病机理中细胞死亡的抑制作用。重要的是，PCD途径与CMV编码的抑制器以进化保守的方式接口，因此鼠和人类CMV的机械相似性。通过与受体相互作用蛋白3（RIP3）激酶在感染细胞中介导的坏死介导的外在凋亡，并通过与两种互锁的CMV细胞死亡抑制剂连接，一种是在感染细胞中发挥的，一种是β植物病毒保守的，并抑制caspase 8激活（VICA）（VICA）（VICA）（VICA）（VICA）最近发现的另一个是通过VICA抑制caspase 8释放的坏死细胞死亡（VIRA）。坏死PCD途径和VICA和Vira之间的关系通过我们的敏锐研究揭示了使用鼠CMV和小鼠突变株的敏锐研究。在这里，我们将研究这些病毒编码的PCD抑制器的相互作用以及它们抑制的同源PCD途径，并确定可能在病原体宿主相互作用中具有广泛意义的关键机制。通过识别该病毒和研究机制编码的RIP3依赖性坏死死亡抑制剂，将确定与人CMV的相关性。我们将确定凋亡和坏死在单核细胞衍生的巨噬细胞感染的最早阶段。以这种方式，我们获得了与宿主防御中凋亡和坏死PCD的保守方面相关的知识和理解，这是当前唯一能够完全阻止病毒并防止感染的免疫机制：特定的目标1将识别人类CMV编码的抑制剂RIP3依赖性坏死并研究了细胞命运结果的外部凋亡抑制剂（caspase 8）和坏死（RIP3）的相互作用，重点是蛋白质蛋白质相互作用和细胞信号传导机制的变化，这些变化引发细胞死亡。具体目的将通过研究VICA的CASP8抑制作用以及蛋白质蛋白相互作用的变化，从而评估Caspase 8和RIP3调节的细胞死亡途径对细胞命运结果的贡献细胞和小鼠坏死。