Mechanisms and Immunological Consequences of Host-Virus Interactions

描述（由申请人提供）：这是一份名为“宿主-病毒相互作用的机制和免疫学后果”的新计划项目（P01）拨款提案。这个项目的共同主题是研究由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，“抗病毒效应和记忆T细胞亚群的分化”（PI: Ulrich von Andrian博士）；项目2，“确定和可视化共刺激对抗病毒免疫的影响”(Co- pi: dr。阿琳·夏普、约翰·惠利和戈登·弗里曼)；项目3，“趋化因子介导的T细胞转运在HIV感染和免疫应答中的作用”(co - pi: dr。安德鲁·Luster， Thorsten Mempel和安德鲁·塔格)；核心A“行政核心”（PI: von Andrian博士）；核心B“活体显微学核心”(co - pi: dr。冯·安德里安和曼佩尔)。每个项目将研究协调T细胞对病毒感染反应的事件序列中的多个步骤：a)在病毒首次进入人体的解剖部位；b)在外周淋巴中，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（LNs）；c)在次级淋巴器官中，幼稚T细胞（Tn）、中枢（Tcm）、效应细胞（Tem）和过渡性记忆细胞（Ttm）返回并由树突状细胞呈递病毒抗原（Ags）；d)初始效应（Teff）反应期间；e)稳态和再挑战时的后续记忆阶段；f)在正常和感染组织的微血管和血管外空间中，选择性地招募（或不招募）经历ag的T细胞亚群，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和沉淀和调节T细胞对病毒攻击的反应的多方面事件的共同长期兴趣，这些pi聚集在一起。该项目的一个决定性特征和核心是由Core B管理的感染成像设备，该设备采用了最先进的多光子活体显微镜（MP-IVM）来成像感染活体小鼠完整组织中的单细胞行为。虽然每个单独的项目都有自己的优点，但它们从与其他项目组件的协同作用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，反过来又受到其他项目组成部分的科学进展的深刻影响。因此，这个PPG提供了我们共同解决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，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.