Mechanisms of Viral Persistence

病毒持续存在的机制

基本信息

批准号：
10056087
负责人：
DAVID G BROOKS
金额：
$ 32.4万
依托单位：
UNIVERSITY HEALTH NETWORK
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056087
关键词：
Address Affect Animal Model Biological Biological Models CD4 Positive T Lymphocytes Chronic Data Disease Disease Progression Environment Event Fostering Funding Goals Grant Growth HIV Health Hepatitis B Virus Hepatitis C Hepatitis Viruses Immune Immune System Diseases Immune response Immunity Immunologics Immunosuppression Infection Inflammation Inflammatory Interferon Type I Journals Lead Legal patent Link Lung Lymphocytic choriomeningitis virus Manuscripts Morbidity - disease rate Mus Mycobacterium tuberculosis Outcome Paper Pathogenicity Pathway interactions Patients Peer Review Plague Predisposition Prevention Publishing Regulation Research Personnel Severities Source T cell differentiation T cell response T-Lymphocyte Tuberculosis Viral Virus Virus Diseases base chronic infection clinically relevant co-infection comparative exhaustion experimental study global health immunoregulation insight mortality mouse model novel pathogen prevent secondary infection

项目摘要

PROJECT SUMMARY/ABSTRACT Chronic viral infections and the co-infections they foster are among the greatest health concerns worldwide. Although their linkage is clear, it is much less clear how one pathogen alters the immune environment to foster another. T cells are critical both to control chronic virus infections and to correctly orchestrate de novo immune responses against co-infecting pathogens. Thus, we surmised that if the immune environment during chronic virus infection altered the ability to appropriately mount T cell responses, that it would jointly and simultaneously affect the chronic infection and susceptibility / severity of secondary infections. The goal of this proposal is to investigate how chronic inflammation and the evolving host:pathogen interactions as viral persistence progresses alters immunity to co-infecting pathogens. To achieve this goal, we have developed a novel mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection and Mycobacterium tuberculosis (Mtb) co-infection. Our preliminary data demonstrate that in the presence of established chronic viral infection, Mtb specific immune responses are delayed, redirected and Mtb replication increased. In the current proposal, we will mechanistically investigate how the modulation of the immune response by the chronic virus spreads to delay acquired Mtb-specific immunity and determine the mechanistic basis through which the altered T cell immunity enhances Mtb disease progression. We will then examine the reciprocal relationship between established Mtb infection and chronic viral co-infection to understand how they comparatively impact the ability to generate and sustain simultaneous immune responses and modulate disease course. The experiments outlined in this proposal will establish important biologic principles and provide a new mechanistic link between the host:pathogen interactions that foster viral persistence with those that enhance susceptibility to and severity of secondary infections. Ultimately, the mechanisms and paradigms we reveal have the potential to lead to new strategies to treat chronic viral infections and the co-infections that plague them.

项目概要/摘要慢性病毒感染及其引发的合并感染是最大的健康问题之一全世界。尽管它们之间的联系很清楚，但尚不清楚一种病原体如何改变培育另一个免疫环境。 T 细胞对于控制慢性病毒感染至关重要并正确协调针对共感染病原体的从头免疫反应。因此，我们推测，如果慢性病毒感染期间的免疫环境改变了免疫能力适当地提高 T 细胞反应，它将共同并同时影响慢性疾病感染和继发感染的易感性/严重程度。该提案的目标是研究慢性炎症和不断进化的宿主：病原体作为病毒如何相互作用持续性进展会改变对共感染病原体的免疫力。为了实现这一目标，我们有开发了一种新型慢性淋巴细胞脉络膜脑膜炎病毒（LCMV）感染小鼠模型和结核分枝杆菌 (Mtb) 合并感染。我们的初步数据表明，在存在已建立的慢性病毒感染，结核分枝杆菌特异性免疫反应延迟，重定向和 Mtb 复制增加。在当前的提案中，我们将机械地研究慢性病毒如何调节免疫反应以延缓传播获得 Mtb 特异性免疫力并确定改变的 T 的机制基础细胞免疫促进结核分枝杆菌疾病的进展。然后我们将检查相互关系已建立的结核分枝杆菌感染和慢性病毒合并感染之间的关系，以了解它们如何相对影响产生和维持同时免疫反应的能力，调节病程。本提案中概述的实验将建立重要的生物学原理并提供宿主与病原体相互作用之间的新机制联系促进病毒持久性，以及增强继发性感染的易感性和严重性感染。最终，我们揭示的机制和范式有可能带来新的结果治疗慢性病毒感染和困扰其的合并感染的策略。