Innate responses following infection with enteric microbes

在全球范围内，每年有400万至600万人死于肠道感染。即使在美国，沙门氏菌 和其他肠胃感染导致数百万人患病，数千人死亡，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 防御病原体的能力。进入肠上皮细胞后，肠道微生物遇到吞噬细胞 产生炎症然而，我们对吞噬细胞如何相互作用、清除和产生 仅来自肠道病原体的炎症是不完全的。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和呈递抗原来增强免疫力，但我们的知识有限， 它们对免疫信号的反应 宿主细胞对细菌的识别是在免疫过程中启动粘膜免疫应答的基础。 感染过程。作为这种相互作用的结果，信号级联在宿主细胞中被激活， 炎症反应和/或附着细菌的吞噬清除。之前，我们发现BAI 1 （脑血管生成抑制剂1）识别细菌脂多糖（LPS）在一个独特的机制，比 Toll样受体4（TLR 4）。BAI 1结合ELMO 1（EnguLfment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 革兰氏阴性菌表达脂多糖（LPS），肠道吞噬细胞能够 区分细菌和肠道病原体。初步结果表明，细菌之间的相互作用 效应分子和ELMO 1调节TNF-α的产生。我的一般假设是， 肠道微生物通过ELMO 1导管信号事件调节宿主免疫反应。 拟议研究的主要目标是了解宿主的微生物感知 吞噬途径，在粘膜中产生不同的先天性反应， 肠道感染这些目标将在以下具体目标中加以实现： 目的1：明确吞噬通路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：确定细菌效应子相互作用在先天免疫中的作用。 拟议的研究将描绘宿主信号通路摄取肠 病原体，与内体信号传导相关并调节免疫应答。因此，他们将提供 涉及细菌效应子调节肠道先天性反应的新机制， 沙门氏菌和其他肠道感染。对微生物相互作用的这些方面的更完整的知识 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， 限制炎症相关疾病。

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.