Necroptosis and adaptive immunity to virus infection

坏死性凋亡和对病毒感染的适应性免疫

基本信息

批准号：
9334693
负责人：
CHRISTOPHER A BENEDICT
金额：
$ 21.55万
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：
2016
资助国家：
美国
起止时间：
2016-08-19 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334693
关键词：
Acute Address Antigen Presentation Antigen-Presenting Cells Antigens Antiviral Agents Antiviral Response Apoptosis Apoptotic Attenuated Binding Biochemical Biological Response Modifiers CD4 Positive T Lymphocytes CD8B1 gene Cell Death Cell Differentiation process Cells Cessation of life Clinical Cross-Priming Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Development Economic Inflation Epitopes Genes HIV vaccine Hand Homeostasis Immune Tolerance Immune response Immune system Immunity Immunologic Memory Infection Inflammation Inflammatory Response Innate Immune Response Link Mediating Memory Modeling Molds Molecular Morphology Murid herpesvirus 1 Muridae Natural Immunity Necrosis Open Reading Frames Pathway interactions Phase Phenotype Population Process RIPK3 gene Reagent Recombinants Rodent Role SIV Shapes System T cell differentiation T cell response T memory cell T-Lymphocyte Testing Time Tissues Vaccine Design Vaccines Vaccinia virus Viral Virus Virus Diseases Work adaptive immune response adaptive immunity base cell suicide gene product immune function immunoregulation in vivo inflammatory milieu inhibitor/antagonist insight mutant pathogen premature prevent programs public health relevance recombinant virus response stem tool vaccine development vector vector vaccine vector-based vaccine vector-induced

项目摘要

DESCRIPTION (provided by applicant): Mechanisms regulating presentation of pathogen-associated antigens to the immune system directly influences the development of protective immunological memory. Programmed cell death is a vital component of the innate immune response, and most pathogens delay, circumvent, or entirely subvert host cell death by encoding inhibitors of these pathways. While one effect of cell suicide is to rapidly prevent pathogen replication and spread, its ramifications on T cell responses are not well understood. Moreover, recent advances have shown that different cell death programs can induce alternative inflammatory responses, which in turn can directly influence antigen presentation and subsequent adaptive immune responses. Here we will address the fundamental question of how different modes of programmed cell death influence adaptive immunity during virus infection in a natural host. Mouse cytomegalovirus (MCMV) is a natural pathogen of murid rodents, and encodes suppressors of both apoptotic and `necroptotic' cell death. Recombinant viruses lacking one or more of these genes are highly attenuated in the host due to premature death of infected cells, but the impact this has on shaping downstream immunity against MCMV are entirely unknown. We hypothesize that different modes of virus-induced programmed cell death will dramatically influence T cell responses at multiple stages. Aim 1 of this project will assess how MCMV epitope-specific CD8 and CD4 T cell differentiation, effector function and memory differs following infection with mutant MCMVs that can't inhibit necroptosis and/or apoptosis. Aim 2 will address whether T cells primed in response to cells dying via these distinct pathways show differential abilities to protect against a heterologous virus infection. This projec will provide new insight into how specific cell death pathways regulate T cell differentiation and memory, and its results will also instruct strategies for rational vaccine design.

描述（由适用提供）：调节病原体相关抗原对免疫系统的机制直接影响受保护的免疫记忆的发展。程序性细胞死亡是先天免疫响应的重要组成部分，大多数病原体延迟，绕过或完全通过编码这些途径的抑制剂来颠覆宿主细胞死亡。虽然细胞自杀的一种作用是迅速防止病原体复制和扩散，但其对T细胞反应的影响尚不清楚。此外，最近的进步表明，不同的细胞死亡程序可以诱导替代性炎症反应，进而可以直接影响抗原表现和随后的适应性免疫调查。在这里，我们将解决自然宿主病毒感染期间不同程序细胞死亡模式如何影响适应性免疫组织化学感染的基本问题。小鼠巨细胞病毒（MCMV）是鼠啮齿动物的天然病原体，编码凋亡和“坏死性”细胞死亡的补充。由于感染细胞过早死亡，缺乏这些基因的重组病毒在宿主中高度减弱，但是这对塑造对MCMV的下游免疫学产生的影响是完全未知的。我们假设病毒诱导的编程细胞死亡的不同模式将在多个阶段显着影响T细胞反应。该项目的目标1将评估MCMV表位特异性CD8和CD4 T细胞分化，效应子功能和记忆分化后如何感染突变的MCMV，无法抑制坏死性和/或凋亡。 AIM 2将解决通过这些不同的途径死亡的细胞启动的T细胞是否显示出可预防异源病毒感染的差异能力。该项目将提供有关特定细胞死亡路径如何调节T细胞分化和记忆的新见解，其结果还将指导理性疫苗设计的策略。