Regulation of Innate Immunity to Enteric Infection

对肠道感染的先天免疫的调节

• 批准号: 7757152
• 负责人: Martin Frederick KAGNOFF
• 金额: $ 24.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7757152
• 关键词: Address; Anatomy; Arts; B-Lymphocytes; Bacillus (bacterium); Biological Models; Blood; Bone Marrow; CCL22 gene; Cell Communication; Cell Separation; Cells; Cellular Immunity; Cessation of life; Characteristics; Chemotactic Factors; Citrobacter rodentium; Collaborations; Colon; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Enteral; Environment; Epithelial; Epithelial Cells; Escherichia coli EHEC; Etiology; Gene Targeting; Genus Cola; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor Receptors; Healed; Histopathology; Human; Image; Immune; Immune response; Immune system; Immunity; Immunohistochemistry; In Vitro; Infection; Inflammatory; Instruction; Intestinal Mucosa; Intestines; Lead; Lesion; Life; Link; Mediating; Mediator of activation protein; Microbe; Microscopy; Modeling; Morbidity - disease rate; Mucositis; Mucous Membrane; Mus; Myeloid Cells; Natural Immunity; Outcome; Pathway interactions; Photons; Population; Production; Regulation; Role; Rotavirus; Rotavirus Infections; Sentinel; Signal Transduction; Signaling Molecule; Site; Small Intestines; T-Lymphocyte; Testing; Tissues; Viral; acquired immunity; base; cytokine; enteric pathogen; enteropathogenic Escherichia coli; healing; in vivo; insight; macrophage-derived chemokine; microbial; microorganism antigen; mouse model; novel; novel strategies; pathogen; prevent; programs; research study; response; sensor; tissue processing

Enteric infections are a major cause of morbidity and death worldwide. The overall goal of Unit 1 is to define key mechanisms that regulate host innate immune defense to enteric infection in the colon and small intestine. Dendritic cells (DC) and intestinal epithelial cells are important mucosal sentinels that initiate immunity to enteric pathogens. We will use two model enteric pathogens to probe DC and DC-epithelial cell communication in the colon and small intestine in vivo. C. rodentium infection, a murine attaching and effacing (A/E) lesion-inducing pathogen, which resembles EPEC and EHEC infection in humans, will be used to probe colonic mucosal responses, and rotavirus, a clinically important viral pathogen will be used to probe small intestinal responses. In preliminary studies, we show that the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) has important non redundant activity in vivo in influencing DC and DC- epithelial cell communication, and governs the character and outcome of the host response to infection with C. rodentium. This led to our hypothesis that GM-CSF has novel activities on DC and epithelial cells in the infected intestinal mucosa that go beyond its previously recognized functions, and determine the outcome of enteric infection. Therefore, an overarching, but not exclusive, goal of the proposed studies includes defining mechanisms by which GM-CSF governs DC and epithelial cell innate responses to enteric pathogens. We will use gene targeted mouse models with in vivo and ex-vivo approaches to address three Specific Aims. Aim 1 will determine mechanisms by which GM-CSF mediates host innate protection to a model A/E pathogen in vivo. Aim 2 will characterize the pathways by which GM-CSF activates production of CCL22, an epithelial cell-produced mediator that is important for GM-CSF-induced DC recruitment and mucosal localization. Aim 3 will determine mechanisms by which DC, epithelial cells and GM-CSF orchestrate host innate immunity and mucosal protection to small intestinal infection in vivo. We will benefit immensely from our collaborations and close interactions with Drs. Eckmann, Raz and Cheroutre by combining our model systems for studies downstream of DC activation, which define mechanisms that link innate and acquired immunity. Our studies require extensive use of the Mouse Model Core, the Histopathology Core (Core B) for tissue processing and immunohistochemistry, and the Imaging and Cell Sorting Core (Core C) for state of the art studies using confocal spectral deconvolution microscopy and live imaging 2-photon microscopy. RELEVANCE (See instructions): Intestinal infections result in extensive morbidity and millions of deaths worldwide each year. Among enteric infections, human A/E pathogens [EPEC and EHEC (the "hamburger bacillus")] and Rotavirus (-800,000 deaths per year) rank among the most frequent causes of dian'heal illness and death. We will determine how the host's innate immune system helps to defend against those infections. We anticipate new infonnation obtained will lead to important and novel approaches for preventing and treating intestinal infections and new insights into the causation of post infectious inflammatory diseases in the intestinal tract.

肠道感染是世界范围内发病和死亡的主要原因。第1单元的总体目标是定义 调节宿主对结肠和小肠中肠道感染的先天免疫防御的关键机制 肠子树突状细胞（DC）和肠上皮细胞是启动肠上皮细胞凋亡的重要粘膜哨兵。 对肠道病原体的免疫力我们将使用两种模式肠道病原体来探测DC和DC-上皮细胞 在体内结肠和小肠中的通信。C.啮齿类感染，一种小鼠附着和 将使用消除（A/E）病变诱导病原体，类似于人类的EPEC和EHEC感染 为了探测结肠粘膜反应，轮状病毒，一种临床上重要的病毒病原体将用于探测 小肠反应。在初步研究中，我们发现，细胞因子粒细胞-巨噬细胞 集落刺激因子（GM-CSF）在体内对DC和DC-2的影响中具有重要的非冗余活性， 上皮细胞通讯，并控制宿主对感染的反应的特征和结果， C.啮齿动物。这导致我们假设GM-CSF对DC和上皮细胞具有新的活性， 受感染的肠粘膜超出了其先前公认的功能，并决定了 肠道感染因此，拟议研究的总体但非唯一目标包括： GM-CSF控制DC和上皮细胞对肠道病原体的先天反应的机制。我们 将使用基因靶向小鼠模型与体内和体外方法，以解决三个具体目标。 目的1将确定GM-CSF介导宿主对模型A/E的先天性保护的机制 体内病原体目的2将描述GM-CSF激活CCL 22产生的途径， 上皮细胞产生的介质，对GM-CSF诱导的DC募集和粘膜 本地化目的3将确定DC、上皮细胞和GM-CSF协调宿主的机制 天然免疫和粘膜保护以抵抗体内小肠感染。我们将受益匪浅， 我们与Eckmann博士，Raz博士和Cheroutre博士的合作和密切互动， 用于研究DC激活下游的系统，其定义了连接先天和获得性的机制 免疫力我们的研究需要广泛使用小鼠模型核心，组织学核心（核心B）， 组织处理和免疫组织化学，以及成像和细胞分选核心（核心C），用于 本领域使用共焦光谱去卷积显微镜和实时成像双光子显微镜进行研究。 相关性（参见说明）： 肠道感染导致广泛的发病率和数以百万计的死亡，每年全世界。在肠道 感染，人类A/E病原体[EPEC和EHEC（“汉堡杆菌”）]和轮状病毒（-800，000例死亡 这些疾病和死亡的最常见原因之一。我们将决定宿主如何 先天免疫系统有助于抵御这些感染。我们预计获得的新信息将导致 预防和治疗肠道感染的重要和新颖的方法，以及对 肠道感染后炎症性疾病的原因。