Mechanisms and Immunological Consequences of Host-Virus Interactions

宿主-病毒相互作用的机制和免疫学后果

基本信息

批准号：
8742510
负责人：
ULRICH H VON ANDRIAN
金额：
$ 197.22万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8742510
关键词：
Acute Address Affect Anatomic Sites Animal Model Antibodies Antiviral Agents Area Biochemical Biological Biological Models Boston CD8B1 gene Cell physiology Cells Chronic Clinical Collaborations Color Complex DNA Recombinant Proteins Dana-Farber Cancer Institute Data Dendritic Cells Effector Cell Equipment Eragrostis Event Funding General Hospitals Generations Genetically Engineered Mouse Goals Grant HIV Infections Home environment Human Human Resources Image Imaging technology Immune response Immune system Immunity Immunologic Surveillance Individual Infection Investigation Joints Lead Life Lymphatic Lymphocyte Lymphoid Lymphoid Tissue Massachusetts Mediating Medical Memory Microscopy Mus National Institute of Allergy and Infectious Disease Nature Organ Outcome Participant Pathway interactions Pennsylvania Peripheral Phase Prophylactic treatment Reagent Recommendation Recruitment Activity Research Research Infrastructure Research Personnel Resources T cell differentiation T cell response T-Lymphocyte T-Lymphocyte Subsets Time Tissues Transitional Cell Translating Travel Viral Viral Antigens Viral Vaccines Virus Virus Diseases Work cell behavior chemokine clinically relevant experience forging human disease interest intravital microscopy lymph nodes medical schools migration multi-photon novel strategies novel therapeutic intervention organizational structure pathogen programs public health relevance research facility response trafficking vaccine development virus host interaction

项目摘要

DESCRIPTION (provided by applicant): This is a proposal for a new Program Project (P01) grant entitled "Mechanisms and Immunological Consequences of Host-Virus Interactions". The common theme in this program is the study of T cell responses that are elicited by acute viral infections. The Program is composed of three Projects and two Cores: Project 1, "Differentiation of Antiviral Effector and Memory T Cell Subsets" (PI: Dr. Ulrich von Andrian); Project 2, "Defining and Visualizing Effects of Costimulation on Antiviral Immunity" (Co- PIs: Drs. Arlene Sharpe, John Wherry and Gordon Freeman); Project 3, "Chemokine-Mediated T Cell Trafficking in HIV Infection and Immune Responses" (Co-PIs: Drs. Andrew Luster, Thorsten Mempel and Andrew Tager); Core A "Administrative Core" (PI: Dr. von Andrian); and Core B "Intravital Microscopy Core" (Co-PIs: Drs. von Andrian and Mempel). Each project will investigate multiple steps in the sequence of events that orchestrate T cell responses to viral infections: a) at the anatomic sites where viruses first enter the body; b) in peripheral lymphatics where free virus, virus-infected target cells and antiviral effector cells travel to draining lymph nodes (LNs); c) in secondary lymphoid organs where naive T cells (Tn), central (Tcm), effector (Tem) and transitional memory cells (Ttm) home and are presented with viral antigens (Ags) by dendritic cells; d) during the initial effector (Teff) response; and e) the subsequent memory phase at steady state and upon rechallenge; and f) in microvessels and the extravascular space of normal and infected tissues where Ag-experienced T cell subsets are selectively recruited (or not) to provide local immune surveillance and a rapid response to reinfections. The PIs were brought together by a common long-standing interest in the function of the immune system and the multi-faceted events that precipitate and regulate T cell responses to viral challenge. A defining feature and centerpiece of this program is the Infectious Imaging facility administered by Core B, which incorporates state-of-the-art multi-photon intravital microscopy (MP-IVM) to image single-cell behavior in intact tissues of living infected mice. Although the individual projects each stand on their own merit, they gain tremendously from synergy with the other Program components. Each Project makes critical scientific contributions to the other two Projects and is, in turn, profoundly impacted by the scientific progress in other Program components. Thus, this PPG provides the means by which we work together to resolve important questions on how viral infections are recognized and remembered. The answers to these questions are of fundamental importance and have the potential to translate into new approaches for the prophylaxis and treatment of a broad spectrum of human diseases.

描述（由申请人提供）：这是题为“宿主病毒相互作用的机制和免疫学后果”的新计划项目（P01）拨款的提案。该项目的共同主题是研究急性病毒感染引起的 T 细胞反应。该计划由三个项目和两个核心组成：项目1，“抗病毒效应子和记忆T细胞亚群的分化”（PI：Ulrich von Andrian博士）；项目 2，“共同刺激对抗病毒免疫的影响的定义和可视化”（共同负责人：Arlene Sharpe 博士、John Wherry 和 Gordon Freeman 博士）；项目 3，“HIV 感染和免疫反应中趋化因子介导的 T 细胞贩运”（联合负责人：Andrew Luster 博士、Thorsten Mempel 和 Andrew Tager 博士）；核心A“行政核心”（PI：冯·安德里安博士）；和核心 B“活体显微镜核心”（联合 PI：von Andrian 博士和 Mempel 博士）。每个项目都将研究协调 T 细胞对病毒感染做出反应的事件序列中的多个步骤：a) 在病毒首先进入人体的解剖部位； b) 在外周淋巴管中，游离病毒、病毒感染的靶细胞和抗病毒效应细胞移动到引流淋巴结（LN）； c) 在次级淋巴器官中，幼稚 T 细胞 (Tn)、中央 T 细胞 (Tcm)、效应细胞 (Tem) 和过渡记忆细胞 (Ttm) 归巢并由树突状细胞呈递病毒抗原 (Ag)； d) 在初始效应器（Teff）响应期间； e) 稳定状态和重新挑战时的后续记忆阶段； f) 在正常组织和感染组织的微血管和血管外空间中，经历过 Ag 的 T 细胞亚群被选择性地招募（或不招募），以提供局部免疫监视和对再感染的快速反应。由于对免疫系统功能以及促进和调节 T 细胞对病毒攻击反应的多方面事件的长期共同兴趣，这些 PI 聚集在一起。该计划的一个决定性特征和核心是由 Core B 管理的感染成像设施，该设施采用最先进的多光子活体显微镜 (MP-IVM)，对活体感染小鼠的完整组织中的单细胞行为进行成像。尽管各个项目都有自己的优点，但它们从与其他计划组成部分的协同作用中获益匪浅。每个项目都对其他两个项目做出了关键的科学贡献，反过来又受到其他计划组成部分的科学进步的深刻影响。因此，这个 PPG 提供了我们共同努力解决如何识别和记住病毒感染的重要问题的方法。这些问题的答案至关重要，并有可能转化为预防和治疗多种人类疾病的新方法。