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：
8984862
负责人：
CHRISTOPHER A BENEDICT
金额：
$ 44.25万
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 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8984862
关键词：
Acute Disease Antibodies Antiviral Agents Apoptosis Attenuated Blocking Antibodies CD4 Positive T Lymphocytes Cells Cessation of life Chronic Cytomegalovirus Cytomegalovirus Infections Data Development Disease Epitopes Equilibrium Family Genes Health Herpesviridae Herpesviridae Infections Homeostasis Host Defense Human Immune Immune System Diseases Immune response Immunity Infection Interleukin-10 Ligands Mediating Murid herpesvirus 1 Mus Mutant Strains Mice Natural Killer Cells Organ Pathway interactions Persons Phase Population Proteins Receptor Signaling Regulation Regulatory T-Lymphocyte Role Salivary Glands Signal Pathway Signal Transduction System T cell response T-Lymphocyte TNF gene TNF-related apoptosis-inducing ligand Testing Viral Viral Proteins Virus Virus Latency Wild Type Mouse Work attenuation cytokine fighting heuristics in vivo killer T cell latent persistent infection mucosal site mutant receptor viral fitness

项目摘要

DESCRIPTION (provided by applicant): Tumor necrosis factor (TNF)-related cytokines are critical for antiviral defense, and are important for maintaining immune homeostasis during chronic infection. Cytomegalovirus (CMV, a ¿-herpesvirus) infection is normally subclinical despite inducing a robust immune response and establishing lifelong persistence/latency, causing acute disease only if host defenses are immature or compromised. CMV accomplishes this by employing many tactics that modulate host immunity, several which target the TNF-family. We have recently identified specific proteins in both human and mouse CMV (MCMV) that inhibit the TNF-related apoptosis inducing ligand (TRAIL) death receptors (UL141 and m166, respectively). A MCMV mutant lacking m166 (MCMV¿m166) shows reduced early replication, suggesting TRAIL-mediated innate defenses are normally neutralized by m166 in vivo. In stark contrast, persistent replication of MCMV¿m166 is enhanced, indicating that viral inhibition of TRAIL DR signaling may promote adaptive immune control of chronic infection. This hypothesis is supported by our results showing that TRAIL-R2-/- mice control MCMV persistence better than wild- type mice. Our identification of specific CMV proteins that inhibit TRAIL DR has revealed new roles for this TNF-related signaling pathway in regulating the early and later phases of a herpesvirus infection. In this proposal we will determine the mechanism(s) by which TRAIL DR signaling, and m166 inhibition of this pathway, function to regulate innate and adaptive immune control of MCMV infection. The fact that both mouse and human CMV encode specific proteins that restrict expression of the TRAIL DR strongly suggests this TNF-related cytokine system regulates CMV infection in humans, and consequently these studies will provide heuristic value.

描述（由适用提供）：肿瘤坏死因子（TNF）相关的细胞因子对于抗病毒防御至关重要，对于在慢性感染过程中维持免疫稳态至关重要。巨细胞病毒（CMV，A€-HERPESVIRUS）的感染通常是亚临床的任务，诱导强大的免疫响应并建立终身持久/潜伏期，仅当宿主防御不成熟或不成熟时，才会导致急性疾病。 CMV A MCMV突变体缺乏M166（MCMV¿M166）显示早期复制减少，这表明TRAIL介导的先天防御通常被M166在Vivo中中和。与之形成鲜明对比的是，MCMV¿M166的持续复制得到了增强，这表明对TRAIL DR信号传导的病毒抑制可能促进对慢性感染的适应性免疫控制。我们的结果支持了这一假设，表明TRAIL-R2 - / - 小鼠控制MCMV持久性比野生型小鼠更好。我们对抑制TRAIL DR的特定CMV蛋白的鉴定已经揭示了这种与TNF相关的信号通路在调节疱疹病毒感染的早期和后期中的新作用。在此提案中，我们将确定TRAIL DR信号传导的机制以及对该途径的M166抑制，以调节MCMV感染的先天和适应性免疫控制。小鼠和人CMV编码限制TRAIL DR表达的特定蛋白质的事实强烈表明，这种与TNF相关的细胞因子系统调节了人类中CMV的感染，因此这些研究将提供启发式价值。