Engulfment of enteric bacteria and the consequences for intestinal inflammation

描述（由申请人提供）：食物和水传播的感染仍然是一个主要的全球健康问题。据世界卫生组织估计，每年有400万至600万人死于肠道感染。即使在美国，沙门氏菌和其他胃肠道感染也导致数百万人患病和数千人死亡。例如，沙门氏菌每年影响1-2百万美国人。然而，我们对吞噬细胞如何相互作用并清除大量复杂的肠道细菌种群的理解是不完整的。吞噬细胞作为免疫防御机制的前线存在，以保护我们的身体免受微生物病原体的侵害。宿主细胞对细菌的识别是感染过程中启动粘膜免疫应答的基础。作为这种相互作用的结果，信号级联在宿主细胞中被激活，导致炎症反应和/或附着细菌的吞噬清除。细菌通过多种模式识别受体（PRRs）与宿主细胞相互作用，PRRs识别微生物产物或病原体相关分子模式（PAMP）。最近，我们发现了一种新的模式识别受体，BAI 1（脑血管生成抑制剂1）。BAI 1优先结合革兰氏阴性菌，并通过激活ELMO 1（吞噬和细胞运动蛋白1）/Rac 1途径促进细菌内化。此外，BAI 1/ELMO 1/Rac 1途径调节先天性细胞因子应答。初步结果显示细菌效应分子和ELMO 1之间的相互作用调节TNF-α的产生。我的一般假设是，BAI 1对革兰氏阴性菌的识别导致ELMO 1介导的信号传导事件，该事件调节细菌摄取和随后的炎症反应。拟议研究的广泛目标是确定细菌吞噬的分子基础，并确定该事件如何影响粘膜中的先天反应和肠道感染的发病机制。这些目标将在以下具体目标中阐述：目标1：确定BAI 1/ELMO 1/Rac 1通路在细菌识别/内化中的作用。目的2：确定调节BAI 1/ELMO 1/Rac 1通路的细菌效应物。目的3：确定BAI 1/ELMO 1/Rac 1在调节宿主反应中的作用。拟议的研究将确定一种新的受体及其相关的吞噬途径摄取肠道病原体并调节随后的炎症的分子基础。因此，它们将提供新的信息，以促进我们对涉及细菌效应子调节与沙门氏菌和其他肠道感染相关的肠道先天反应的机制的理解。对微生物发病机理的这些方面的更全面的了解可能会导致新的治疗方法，限制病原菌的易位和局部炎症反应引起的组织损伤。

DESCRIPTION (provided by applicant): Food and water-borne infections remain a major global health problem. According to the estimates of the World Health Organization, 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 and thousands of deaths. For example, Salmonella affects 1-2 million Americans each year. However, our understanding about how phagocytes interact and clear the vast, complex populations of enteric bacteria is incomplete. Phagocytes are present as the front line of the immune defense mechanisms to protect our body from microbial pathogens. 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. Bacteria interact with host cells via multiple pattern recognition receptors (PRRs) which recognize microbial products or pathogen-associated molecular patterns (PAMPs). Recently we identified a new pattern recognition receptor, BAI1 (Brain Angiogenesis Inhibitor 1). BAI1 preferentially binds Gram-negative bacteria and contributes to bacterial internalization by activating the ELMO1 (Engulfment and cell motility protein 1)/Rac1 pathway. Moreover, the BAI1/ELMO1/Rac1 pathway regulates innate cytokine responses. Preliminary results show that interactions between bacterial effector molecules and ELMO1 modulate TNF-a production. My general hypothesis is that the recognition of Gram-negative bacteria by BAI1 leads to ELMO1-mediated signaling events that regulate bacterial uptake and the subsequent inflammatory responses. The broad objectives for the proposed studies are to define the molecular basis of bacterial engulfment and determine how this event impacts 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 BAI1/ELMO1/Rac1 pathway in bacterial recognition/internalization. Aim 2: Determine the bacterial effectors that regulate the BAI1/ELMO1/Rac1 pathway. Aim 3: Define the role of the BAI1/ELMO1/Rac1 in regulating host responses. The proposed studies will define the molecular basis whereby a novel receptor and its associated engulfment pathway uptakes enteric pathogens and regulates subsequent inflammation. As such, they will provide new information to advance our understanding of a 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 pathogenesis may lead to new therapies that limit the translocation of pathogenic bacteria and the tissue damage induced by local inflammatory responses.