Mechanisms and Immunological Consequences of Host-Virus Interactions

描述（由申请人提供）：这是一个新的计划项目（P01）资助的建议，题为“宿主-病毒相互作用的机制和免疫学后果”。 该计划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，“共刺激对抗病毒免疫的定义和可视化效果”（共同主要研究者：Arlene Sharpe、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细胞运输”（共同PI：Andrew Luster博士、Thorsten Mempel博士和Andrew Tager博士）;核心A“行政核心”（主要研究者：冯安德里安博士）和核心B“活体显微镜核心”（共同主要研究者：冯安德里安博士和Mempel博士）。 每个项目都将研究协调T细胞对病毒感染反应的事件序列中的多个步骤：a）在病毒首次进入体内的解剖部位; B）在游离病毒、病毒感染的靶细胞和抗病毒效应细胞前往引流淋巴结（LN）的外周淋巴系统; c）在次级淋巴器官中，其中幼稚T细胞（Tn）、中枢（Tcm）、效应细胞（Tem）和过渡记忆细胞（Ttm）归巢并由树突细胞呈递病毒抗原（Ag）;和e）在稳态和再激发时的随后记忆期;和f）在正常和感染组织的微血管和血管外空间中，其中Ag-经历的T细胞亚群被选择性地募集（或不募集）以提供局部免疫监视和对再感染的快速应答。 PI是由对免疫系统功能的共同长期兴趣以及沉淀和调节T细胞对病毒攻击的反应的多方面事件聚集在一起的。 该计划的一个定义性特征和核心是由核心B管理的感染性成像设施，该设施采用了最先进的多光子活体显微镜（MP-IVM），对活感染小鼠完整组织中的单细胞行为进行成像。 虽然每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重要的科学贡献，反过来又受到其他项目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忆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广泛人类疾病的新方法。

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.