Innate responses following infection with enteric microbes

全球每年有400-600万人死于肠道感染。即使在美国，沙门氏菌 其他胃肠道感染导致数百万人患病，数千人死亡，数十亿美元 来自食品召回和医院相关费用的支出。先天免疫系统是第一条线 对病原体的防御。肠道微生物进入肠道上皮细胞后，会遇到吞噬细胞 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 仅由肠道病原体引起的炎症是不完整的。内体系统将先天与适应性联系起来 通过降解致病微生物和呈递抗原来免疫，但我们的知识仅限于 它们对免疫信号的反应。 宿主细胞对细菌的识别是启动粘膜免疫反应的基础 感染过程。这种相互作用的结果是，在宿主细胞中激活了信号级联 对炎症反应和/或附着细菌的吞噬清除。此前，我们发现BAI1 (脑血管生成抑制因子1)识别细菌脂多糖(LPS)的机制比 众所周知的Toll样受体4(TLR4)。BAI1与ELMO1(吞噬和细胞运动蛋白1)结合， 促进细菌的吞噬，并引发炎症反应。虽然致病和致病 共生革兰氏阴性菌表达内毒素(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调节肿瘤坏死因子-α的产生。我的一般假设是感觉到 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和发病机制 肠道感染。这些目标将通过以下具体目标加以解决： 目的1：明确吞噬途径在宿主炎症反应中的作用。 目的2：确定调节吞噬途径的细菌效应物。 目的3：明确细菌效应器相互作用在先天性免疫中的作用。 拟议的研究将描绘宿主信号通路摄取肠道的分子基础。 病原体与内体信号传递相关，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。更全面地了解微生物相互作用的这些方面 与生俱来的免疫系统将导致抗菌素耐药性感染的靶向治疗，并广泛地 限制与炎症相关的疾病。

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.