BACTERIAL CAPTURE AND ANTIGEN PRESENTATION IN SPLEEN

描述(申请人提供)：临床观察和实验动物模型表明，脾是宿主对血液传播细菌免疫反应的重要部位。脾独特的组织结构和常驻髓系细胞和淋巴样细胞的多样化混合物如何在体内协同工作以对抗感染仍知之甚少。我们期望天然的组织环境以复杂和深刻的方式调节免疫细胞的功能，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组织学分析，我们建议研究早期吞噬细胞清除机制，分析脾吞噬细胞的运输和趋化因子信号在脾重塑中的作用，并确定参与向T细胞递呈细菌特异性抗原的抗原提呈细胞(APC)和组织微环境。我们的总体目标是了解脾结构如何影响免疫功能。我们的假设是，在边缘区域的早期宿主和病原体的相互作用在一些细胞中诱导杀菌反应，而在另一些细胞中，这些相互作用触发细胞迁移到适当的组织微室以递送抗原。我们的研究将使用细菌感染的李斯特氏菌模型，在该模型中，脾感染导致T细胞启动，并诱导持久免疫。拟议的研究将增强我们对脾如何对血液传播细菌做出反应的基本理解，并为未来研究其他更具毒性的人类病原体提供一个框架。公共卫生相关性：脾是人体内最大的淋巴细胞集合，在对细菌的免疫中发挥着重要作用。然而，关于常驻免疫细胞如何协同工作来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细菌在脾中的捕获，并了解细菌抗原是如何呈现给T细胞的。

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.