BACTERIAL CAPTURE AND ANTIGEN PRESENTATION IN SPLEEN

描述（由申请人提供）：临床观察和实验动物模型表明脾脏是宿主对血源性细菌免疫反应的重要部位。脾脏独特的组织结构和骨髓细胞和淋巴细胞的多样化混合物如何在体内共同对抗感染仍然知之甚少。我们期望原生组织环境以复杂而深刻的方式调节免疫细胞功能，因此体内成像方法是生化和体外研究的重要补充。利用双光子显微镜和强大的组织学分析，我们建议研究早期的吞噬细胞清除机制，分析脾脏吞噬细胞的运输和趋化因子信号在脾脏重塑中的作用，并确定抗原呈递细胞（APCs）和组织微环境参与向T细胞呈递细菌特异性抗原。我们的总体目标是了解脾脏结构如何影响免疫功能。我们的假设是，在边缘区早期宿主-病原体相互作用在一些细胞中诱导了杀菌反应，而在其他细胞中，这些相互作用触发细胞迁移到适当的组织微室进行抗原呈递。我们的研究将使用具有良好特征的细菌感染李斯特菌模型，其中脾脏感染导致T细胞启动并诱导持久免疫。拟议的研究将增强我们对脾脏如何对血源性细菌作出反应的基本理解，并为未来研究其他更致命的人类病原体提供框架。公共卫生相关性：脾脏是人体最大的淋巴细胞集合，在对细菌的免疫中起着重要作用。然而，关于驻留免疫细胞如何协同工作以启动宿主对感染的免疫反应的细节知之甚少。我们将使用尖端的单细胞成像技术来研究脾脏中细菌的捕获，并了解细菌抗原如何呈现给T细胞。

DESCRIPTION (provided by applicant): Clinical observations and experimental animal models implicate the spleen as an important site for host immune responses to blood-borne bacteria. How the spleen's unique tissue structure and the diverse mixture of resident myeloid and lymphoid cells work together in vivo to combat infection remains poorly understood. We expect the native tissue environment to regulate immune cell function in complex and profound ways and therefore in vivo imaging approaches are a crucial complement biochemical and in vitro studies. Using two-photon microscopy and a robust histological analysis, we propose to investigate early phagocyte clearance mechanisms, analyze the trafficking of splenic phagocytes and the role of chemokine signaling in spleen remodeling, and identify the antigen presenting cells (APCs) and tissue microenvironment involved in presenting bacteria-specific antigen to T cells. Our overall goal is to understand how spleen structure impacts immune function. Our hypothesis is that early host-pathogen interactions in the marginal zone induce bactericidal responses in some cells, while in others, those interactions trigger cell migration to the appropriate tissue microcompartments for antigen presentation. Our studies will use the well characterized Listeria model of bacterial infection, in which splenic infection leads to T cell priming and induces long-lasting immunity. The proposed studies will enhance our fundamental understanding of how the spleen responds to blood-borne bacteria and provide a framework for future studies of other more virulent human pathogens. PUBLIC HEALTH RELEVANCE: The spleen is the largest collection of lymphocytes in the human body and plays an important role in immunity to bacteria. However, few details are known regarding how resident immune cells work together to initiate the host immune response to infection. We will use cutting edge single-cell imaging techniques to study the capture of bacteria in the spleen and understand how bacterial antigen is presented to T cells.