Innate responses following infection with enteric microbes

肠道微生物感染后的先天反应

• 批准号: 9175916
• 负责人: Soumita Das
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175916
• 关键词: Address; Angiogenesis Inhibitors; Antigen-Presenting Cells; Antigens; Antimicrobial Resistance; Area; Bacteria; Benign; Binding; Biochemical; Brain; CCL2 gene; CD14 gene; Cecum; Cells; Cessation of life; Confocal Microscopy; Data; Disease; Enteral; Epithelial Cells; Escherichia coli Infections; Event; Expenditure; Extracellular Domain; Family; Food; Goals; Gram-Negative Bacteria; Homeostasis; Hospitals; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Intestinal Mucosa; Intestines; Investigation; Knowledge; Lead; Link; Lipid A; Lipopolysaccharides; Microbe; Modeling; Molecular; Morbidity - disease rate; Mucosal Immune Responses; Mucous Membrane; Mus; Myeloid Cells; Natural Immunity; Organism; Outcome; Pathogenesis; Pathogenicity Island; Pathway interactions; Pattern recognition receptor; Phagocytes; Process; Production; Proteins; Receptor Signaling; Research; Role; Salmonella; Salmonella infections; Signal Pathway; Signal Transduction; Signaling Molecule; Spleen; System; TLR4 gene; TNF gene; Tail; Testing; Therapeutic Intervention; Tissues; United States; Virulence Factors; Water; adaptive immunity; base; cell motility; cytokine; design; differential expression; enteric pathogen; foodborne; ileum; insight; intestinal homeostasis; macrophage; microbial; microbial community; microbiota; microorganism interaction; mortality; mutant; new therapeutic target; novel; novel strategies; pathogen; pathogenic bacteria; response; targeted treatment; uptake

Globally, 4-6 million people die of enteric infections each year. Even within the United States, Salmonella and other gastroenteric infections are responsible for millions of illness, thousands of deaths and billion-dollar of expenditure from food recall and hospital associated expenses. The innate immune system is the first line of defense against pathogens. After entering intestinal epithelial cells, enteric microbes encounter phagocytes and generate inflammation. However, our understanding about how phagocytes interact, clear, and generate inflammation only from the enteric pathogen is incomplete. Endosomal systems connect innate to adaptive immunity by degrading the pathogenic microbe and presenting the antigens but our knowledge is limited to their responses to immune signaling. Bacterial recognition by host cells is fundamental for the initiation of mucosal immune responses during the infection process. As a consequence of this interaction, signaling cascades are activated in host cells that lead to inflammatory responses and/or phagocytic clearance of attached bacteria. Previously, we found that BAI1 (Brain Angiogenesis Inhibitor 1) recognizes bacterial lipopolysaccharide (LPS) in a unique mechanism than the well-known Toll like receptor 4 (TLR4). BAI1 binds ELMO1 (EnguLfment and cell Motility protein 1) that facilitates the engulfment of bacteria and induces inflammatory responses. While both pathogenic and commensal-Gram-negative bacteria express lipopolysaccharide (LPS), intestinal phagocytes are able to discriminate commensals from enteric pathogens. Preliminary results show that interactions between bacterial effector molecules and ELMO1 modulate TNF-α production. My general hypothesis is that the sensing of enteric microbes by ELMO1 conduits signaling events that regulate host immune responses. The broad objectives for the proposed studies are to understand the microbial sensing by the host engulfment pathway that generates differential innate responses in the mucosa and the pathogenesis of enteric infections. These objectives will be addressed in the following Specific Aims: Aim 1: Define the role of the engulfment pathway in host inflammatory responses. Aim 2: Determine the bacterial effectors that regulate the engulfment pathway. Aim 3: Define the role of bacterial effector interactions in innate immunity. The proposed studies will delineate the molecular basis whereby a host signaling pathway uptakes enteric pathogens, associates with endosomal signaling and regulates immune responses. As such, they will provide new mechanism involving bacterial effectors in regulating intestinal innate responses that are relevant to Salmonella and other enteric infections. A more complete knowledge of these aspects of microbial interaction with innate immune system will lead to targeted therapies for antimicrobial resistant infections and broadly to limit inflammation-linked diseases.

全球每年有 4-600 万人死于肠道感染。即使在美国境内，沙门氏菌 和其他胃肠道感染导致数百万人患病、数千人死亡和数十亿美元的损失 食品召回和医院相关费用的支出。先天免疫系统是第一道防线 防御病原体。肠道微生物进入肠上皮细胞后，遇到吞噬细胞 并产生炎症。然而，我们对吞噬细胞如何相互作用、清除和生成的理解 仅来自肠道病原体的炎症是不完整的。内体系统将先天性与适应性联系起来 通过降解病原微生物并呈递抗原来获得免疫力，但我们的知识仅限于 他们对免疫信号的反应。 宿主细胞对细菌的识别对于在感染过程中启动粘膜免疫反应至关重要。 感染过程。由于这种相互作用，宿主细胞中的信号级联被激活，导致 炎症反应和/或附着细菌的吞噬清除。之前我们发现BAI1 （脑血管生成抑制剂 1）以独特的机制识别细菌脂多糖 (LPS) 众所周知的 Toll 样受体 4 (TLR4)。 BAI1 结合 ELMO1（吞噬和细胞运动蛋白 1）， 促进细菌的吞噬并诱导炎症反应。虽然致病性和 共生革兰氏阴性菌表达脂多糖（LPS），肠道吞噬细胞能够 区分共生菌和肠道病原体。初步结果表明，细菌之间的相互作用 效应分子和 ELMO1 调节 TNF-α 的产生。我的一般假设是 肠道微生物通过 ELMO1 传导调节宿主免疫反应的信号事件。 拟议研究的主要目标是了解宿主对微生物的感知 吞噬途径在粘膜中产生不同的先天反应及其发病机制 肠道感染。这些目标将在以下具体目标中得到解决： 目标 1：确定吞噬途径在宿主炎症反应中的作用。 目标 2：确定调节吞噬途径的细菌效应子。 目标 3：定义细菌效应子相互作用在先天免疫中的作用。 拟议的研究将描述宿主信号通路摄取肠溶的分子基础 病原体，与内体信号传导相关并调节免疫反应。因此，他们将提供 涉及细菌效应物调节肠道先天反应的新机制 沙门氏菌和其他肠道感染。对微生物相互作用的这些方面有更完整的了解 与先天免疫系统的结合将导致针对抗生素耐药性感染的靶向治疗，并广泛应用于 限制与炎症相关的疾病。