The role of TRAIL in immune control of cytomegalovirus

TRAIL在巨细胞病毒免疫控制中的作用

• 批准号: 10624385
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624385
• 关键词: Acute; Apical; 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; Persons; 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

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。

项目成果

Inhibition of the TRAIL death receptor by CMV reveals its importance in NK cell-mediated antiviral defense.

• DOI: 10.1371/journal.ppat.1004268
• 发表时间: 2014-08
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Verma S;Loewendorf A;Wang Q;McDonald B;Redwood A;Benedict CA
• 通讯作者: Benedict CA

CMV immune evasion and manipulation of the immune system with aging.

• DOI: 10.1007/s11357-017-9986-6
• 发表时间: 2017-06
• 期刊: GeroScience
• 影响因子: 5.6
• 作者: Jackson SE;Redeker A;Arens R;van Baarle D;van den Berg SPH;Benedict CA;Čičin-Šain L;Hill AB;Wills MR
• 通讯作者: Wills MR

Neutrophils recruited by IL-22 in peripheral tissues function as TRAIL-dependent antiviral effectors against MCMV.

• DOI: 10.1016/j.chom.2014.03.003
• 发表时间: 2014-04-09
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Stacey MA;Marsden M;Pham N TA;Clare S;Dolton G;Stack G;Jones E;Klenerman P;Gallimore AM;Taylor PR;Snelgrove RJ;Lawley TD;Dougan G;Benedict CA;Jones SA;Wilkinson GW;Humphreys IR
• 通讯作者: Humphreys IR

Late-rising CD4 T cells resolve mouse cytomegalovirus persistent replication in the salivary gland.

• DOI: 10.1371/journal.ppat.1011852
• 发表时间: 2024-01
• 期刊: PLoS pathogens
• 影响因子: 6.7

A noncanonical function of cGAMP in inflammasome priming and activation.

• DOI: 10.1084/jem.20171749
• 发表时间: 2017-12-04
• 期刊: The Journal of experimental medicine
• 作者: Swanson KV;Junkins RD;Kurkjian CJ;Holley-Guthrie E;Pendse AA;El Morabiti R;Petrucelli A;Barber GN;Benedict CA;Ting JP
• 通讯作者: Ting JP