T-cell immunity to polyomavirus infection

T细胞对多瘤病毒感染的免疫

基本信息

批准号：
8515330
负责人：
Aron Eliot Lukacher
金额：
$ 35.96万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-23 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515330
关键词：
AIDS/HIV problem Acute Affinity Aging Animals Antigens Antiviral Agents Antiviral Therapy Autoimmune Process BK Virus Binding CD4 Positive T Lymphocytes CD8B1 gene Cell Cycle Kinetics Cells Crohn&apos s disease Cutaneous Data Defect Demyelinating Diseases Depressed mood Disabled Persons Disease Dysplasia Epitopes Evolution Flow Cytometry Functional disorder Funding Gene Chips Gene Silencing Generations Genes Genetic Genome Goals HIV-1 Herpesviridae Human Immune Immunity Immunocompetent Immunosuppression Immunotherapy Individual Infection Inflammation Inflammatory JC Virus Kidney Diseases Kidney Transplantation Kinetics Life Ligands Lymphoid MHC binding peptide Malignant Neoplasms Mediating Memory Merkel cell carcinoma Modeling Molecular Multiple Sclerosis Mus Natural Immunity Organ Output Pathogenesis Patients Peptide/MHC Complex Polyomaviridae Polyomavirus Polyomavirus Infections Population Progressive Multifocal Leukoencephalopathy Proteins Psoriasis Recruitment Activity Research Resistance Respiratory Tract Infections Secondary to Signal Transduction Skin Species Specificity Staging System T cell differentiation T cell response T memory cell T-Lymphocyte Technology Testing Transgenic Mice Transgenic Organisms Tropism Variant Vertebrates Viral Antigens Virus Virus Diseases Western Blotting adaptive immunity effective therapy handicapping condition innovation kidney allograft lytic replication mortality mouse polyomavirus mutant novel parent grant pathogen residence response retroviral transduction self-renewal therapy development trafficking tumor tumorigenesis virome

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this renewal application is to understand the mechanisms responsible for generating and maintaining antiviral CD8 T cell responses required to contain persistent "smoldering" viral infections. Persistent virus infections may be categorized into those that are chronically viremic (e.g., HIV-1) and those that maintain themselves by repetitive cycles of reactivation of lytic replication from a noninfectious latent state (e.g., herpesviruses). Polyomaviruses (PyV), silent residents of the "virome" of many vertebrates including humans, persist in a low-level infectious state. However, under conditions of immunosuppression human PyVs can incur life-threatening disease. BK virus is a significant cause of kidney transplant dysfunction and loss. A major cause of mortality in the HIV/AIDS population, JC virus-induced Progressive Multifocal Leukoencephalopathy (PML) has recently emerged in individuals receiving humoral immunotherapies for autoimmune and inflammatory diseases (e.g., multiple sclerosis, Crohn's disease, and severe psoriasis). Several new human PyVs have also recently been isolated from nonbacterial respiratory infections and as a likely causative agent for an aggressive fatal cutaneous malignancy. No effective therapies for PyV infection are available. Due to the tight species specificity of Polyomaviridae that restricts infection to natural animal reservoirs, we have an incomplete understanding of the immune mechanisms needed to keep these smoldering infections in check. Using mouse polyomavirus (MPyV), we discovered that na¿ve virus-specific CD8 T cells are recruited during persistent infection. Data generated in the last funding cycle reveal that temporal differences in recruitment dramatically modulate the quality of the memory T cell compartment. We hypothesize that dynamic changes over the course of infection govern whether MPyV-specific CD8 T cells differentiate into competent memory cells, which, in turn, will be reflected at their levels of gen expression and the TCR-CD8-peptide:MHC tri-molecular interaction. Understanding the mechanisms that control the generation of durable anti-MPyV CD8 T cell memory may help in the development of interventions to enhance immunity to human PyV infections. We will test the above hypothesis in the following three Specific Aims: Aim 1: To define determinants regulating the contribution of acute vs. persistent infection-recruited antiviral CD8 T cells to the memory population. Aim 2: To determine molecular signaling mechanisms underlying the functional differences between acute and persistent infection-recruited MPyV-specific CD8 T cells. Aim 3: To define molecular differences between MPyV-specific memory T cells recruited during acute and persistent infection.

描述（由应用程序提供）：此更新应用的长期目标是了解负责产生和维持抗病毒CD8 T细胞反应所需的机制，以包含持续的“闷烧”病毒感染。持续的病毒感染多瘤病毒（PYV），包括人类在内的许多脊椎动物的“病毒素”的沉默居民一直处于低水平的感染状态。但是，在免疫抑制条件下，人PYV会引起威胁生命的疾病。 BK病毒是肾脏移植功能障碍和丧失的重要原因。 JC病毒诱导的进行性多灶性白细胞掌病（PML）的主要原因是接受自身免疫性和炎症性疾病的体液免疫疗法的个体（例如，多发性硬化症，克罗恩病，克罗恩病，以及严重的负典型的负责人）。最近还从非细菌呼吸道感染中分离出几种新的人类PYV，并可能是致命的致命皮肤恶性肿瘤的灾难性剂。没有有效的PYV感染疗法。由于将感染限制在天然动物储层的多瘤病毒的特异性紧密，因此我们对控制这些闷热感染所需的免疫机制有不完全的理解。使用小鼠多瘤病毒（MPYV），我们发现在持续感染期间募集了NA¿VE病毒特异性CD8 T细胞。在上一个融资周期中产生的数据表明，招募的暂时差异动态调节内存T细胞室的质量。我们假设动态变化在感染过程中，MPYV特异性的CD8 T细胞是否分化为主管的记忆细胞，这反过来又将反映在其Gen表达水平和TCR-CD8肽：MHC Tri-Tri分子相互作用中。了解控制耐用的抗MPYV CD8 T细胞记忆的机制可能有助于开发干预措施，以增强对人PYV感染的免疫力。我们将在以下三个特定目的中检验上述假设：目标1：确定急性感染与持续感染的抗病毒CD8 T细胞对记忆群的贡献。目的2：确定急性和持续感染已重新征收的MPYV特异性CD8 T细胞之间功能差异的分子信号传导机制。目标3：定义在急性和持续感染期间募集的MPYV特异性记忆T细胞之间的分子差异。