The role of TRAIL in immune control of cytomegalovirus

TRAIL在巨细胞病毒免疫控制中的作用

基本信息

批准号：
10180877
负责人：
CHRISTOPHER A BENEDICT
金额：
$ 54.9万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-10 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180877
关键词：
Acute Antiviral Agents CD4 Positive T Lymphocytes Cell Death Cells Cercopithecine Herpesvirus 1 Cessation of life Clinical Cytomegalovirus Cytomegalovirus Infections Data Defense Mechanisms Detection Development Disease Epitopes Equilibrium Family Gene Expression Profile Health Herpesviridae Human Immune Immune System Diseases Immune response Immune signaling Immune system Immunity Infection Inflammation Lymphoid Cell Mediating Mucous Membrane Mus Mutate Natural Killer Cells Nature Pathway interactions Phase Play Population Process Proteins Receptor Signaling Role Salivary Glands Signal Pathway Signal Transduction System T cell differentiation T cell response TNF gene TNF-related apoptosis-inducing ligand TNFSF10 gene Techniques Testing Time Tissues Viral Viral Proteins Virus Virus Diseases adaptive immune response cell type chronic infection cytokine fighting heuristics in vivo mutant receptor response tool transcriptome sequencing viral fitness

项目摘要

Summary Cytomegalovirus (CMV, a b-herpesvirus) establishes a persistent infection that is endemic in humans and mice. CMV causes acute clinical disease only if immunity is naïve or compromised, exemplifying how coevolution with its host over millennia has resulted in a largely non-pathogenic détente. The nature of this détente is dependent upon the many strategies that CMV uses to subvert detection by the immune system. TNF-related cytokines are key regulators of antiviral defenses, and we have shown that both mouse and human CMV (MCMV and HCMV) inhibit expression of the TNF-related apoptosis inducing ligand death-receptors (TRAIL-DR) via the M166 and UL141 viral proteins, respectively. Viral mutants lacking these proteins are highly sensitive to control by TRAIL-expressing innate immune cells during the early-phase of CMV infection. In contrast, if MCMV is unable to restrict TRAIL-DR signaling via M166, the duration of persistent replication is dramatically longer. This is likely due to an altered CD4 T cell response that is unable to resolve persistence within the normal time frame. Together, our past and new results place the TRAIL signaling system at a critical apex in regulating various phases of the immune response to persistent virus infection. This proposal will reveal the how this TNF-family cytokine regulates antiviral immune defenses, and will help to define their broader importance in regulating inflammation and cell death.

概括巨细胞病毒（CMV，A B-Herpesvirus）建立了一种持续的感染，该感染在人类中是内在的和老鼠。 CMV仅在免疫学是幼稚或妥协的情况下才会引起急性临床疾病几千年来，与其宿主的共同进化如何导致很大程度上的非致病性détente。这这种détente的性质取决于CMV用来颠覆检测的许多策略免疫系统。与TNF相关的细胞因子是抗病毒防御的关键调节剂，我们有表明小鼠和人CMV（MCMV和HCMV）都抑制了TNF相关的表达细胞凋亡通过M166和UL141病毒蛋白诱导配体死亡受体（TRAIL-DR），缺乏这些蛋白质的病毒突变体对通过表达跟踪的控制高度敏感 CMV感染早期期间的先天免疫细胞。相反，如果MCMV无法限制通过M166进行TRAIL-DR信号传导，持续复制的持续时间大大更长。这可能是由于CD4 T细胞响应的改变，无法在正常时间内解决持久性框架。一起，我们的过去和新结果将步道信号系统放在关键的先端调节免疫反应对持续病毒感染的各个阶段。该提议将揭示这种TNF家庭细胞因子调节抗病毒免疫防御的方式，并将有助于定义其在控制炎症和细胞死亡方面更加重要。