Mechanisms and Immunological Consequences of Host-Virus Interactions

描述(由申请人提供)：这是一项新的计划项目(P01)拨款的建议，题为“宿主-病毒相互作用的机制和免疫学后果”。这个项目的共同主题是研究由急性病毒感染引发的T细胞反应。该方案由三个项目和两个核心组成：项目1，“抗病毒效应器和记忆T细胞亚群的分化”(共同参与项目：Ulrich von Andrian博士)；项目2，“确定和可视化协同刺激对抗病毒免疫的影响”(共同参与项目：Arlene Sharpe、John Wherry和Gordon Freeman博士)；项目3，“趋化因子介导的T细胞在艾滋病毒感染和免疫反应中的贩运”(共同参与项目：Andrew Luster、Thorsten Mempel和Andrew Tager博士)；核心A“行政核心”(共同参与项目：安德鲁·卢斯特博士、Thorsten Mempel和Andrew Tager博士)；核心B“活体内显微镜核心”(Co-Pis：Dr.von Andrian和Mempel)。每个项目都将研究协调T细胞对病毒感染的反应的事件序列中的多个步骤：a)在病毒首次进入人体的解剖部位；b)在外周淋巴管中，在那里游离病毒、感染病毒的靶细胞和抗病毒效应细胞移动到引流淋巴结(LNS)；c)在次级淋巴器官中，原始T细胞(Tn)、中枢(Tcm)、效应器(Tem)和过渡性记忆细胞(TTM)聚集在这里，树突状细胞(DC)呈递病毒抗原(Ags)；d)在初始效应器(TEff)反应期间；以及e)随后的记忆阶段，处于稳定状态和重新激发时；和f)在正常和感染组织的微血管和血管外空间，选择性地招募(或不招募)经历过Ag的T细胞亚群，以提供局部免疫监视和对再次感染的快速反应。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细胞对病毒挑战的反应的多方面事件而结合在一起的。该计划的一个主要特点和核心是由Core B管理的传染病成像设施，该设施结合了最先进的多光子活体显微镜(MP-IVM)，以成像活着感染小鼠的完整组织中的单细胞行为。虽然每个单独的项目都有各自的优点，但它们从与其他计划组成部分的协同中获得了巨大的收益。每个项目都对其他两个项目做出了重要的科学贡献，并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，这一PPG提供了我们共同努力解决有关如何识别和记住病毒感染的重要问题的手段。这些问题的答案具有根本性的重要性，有可能转化为预防和治疗广泛的人类疾病的新方法。

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.