Tolerance defenses in host-microbiota interactions

项目摘要 这项建议的总体目标是了解宿主在感染期间的代谢适应如何促进共同- 宿主和肠道病原体之间的操作防御，以驱动无症状的携带和最终的 共生主义的演变。拟议的研究利用了一种涉及肠道的自然体内宿主病原体。 引起传染性结肠炎的细菌病原体。在之前的工作中，Ayres实验室发现该主机 肠道病原体感染期间微量营养素的代谢适应，调节宿主碳水化合物 新陈代谢导致了艾尔斯实验室称之为“新陈代谢贿赂”的现象。这涉及到分配 碳水化合物进入病原体的生态位(肠道)，以增加病原体代谢的有效性。 艾尔斯实验室发现，病原体对这些特定碳水化合物的新陈代谢受到抑制。 病原菌的致病力和致病力，表明这种微量营养素对寄主和病原菌的大量营养素的调节 新陈代谢起到了抗毒力机制的作用。在新的提案中，艾尔斯实验室展示了令人兴奋的数据 证明微量营养素代谢协调宿主葡萄糖和脂肪之间的相互作用 新陈代谢抑制毒力，促进与肠道病原体的合作。拟议的研究将 探讨膳食微量营养素调节常量营养素代谢抑制作用的机制 病原菌的致病力以产生无症状的病原体携带者。拟议的研究将集中于 了解微量营养素代谢如何协调体内的葡萄糖和脂肪过程以抑制 病原体的致病力。拟议的研究将检验获得性免疫之间的相互作用 反应和微量营养素介导的协同防御，阐明了这两个系统是如何合作的 调节健康的宿主和病原体的相互作用，防止感染性结肠炎。最后，拟议的研究将 利用这一新的寄主-病原体/微量营养素系统来阐明驱动细菌进化的机制 病原菌在微生物区系内朝着共生和持久性的方向衰减。这项工作将对 为了更好地了解胃肠黏膜适应性免疫学，急性和慢性的发病机制 胃肠道炎症和结肠炎，胃肠道微生物和微生物代谢的影响 胃肠健康与疾病，包括致病细菌对病原体的影响。

Project Summary The overall goal of this proposal is to understand how host metabolic adaptations during infection promote co- operative defenses between a host and enteric pathogens to drive asymptomatic carriage and the eventual evolution of commensalism. The proposed studies utilize a natural in vivo host-pathogen involving a enteric bacterial pathogen that causes infectious colitis. In previous work, the Ayres lab discovered that host micronutrient metabolic adaptations during infection with enteric pathogens, regulates host carbohydrate metabolism leading to a phenomenon the Ayres lab calls “metabolic bribery”. This involves the allocation of carbohydrates to the niche of the pathogen (intestine) to increase availability for the pathogen to metabolize. The Ayres lab discovered that the metabolism of these specific carbohydrates by the pathogen suppressed pathogen virulence and disease, indicating this micronutrient regulation of host and pathogen macronutrient metabolism acts as an anti-virulence mechanism. In the new proposal, the Ayres lab presents exciting data demonstrating that micronutrient metabolism coordinates interactions between host glucose and lipid metabolism to suppress virulence and promote cooperation with enteric pathogens. The proposed studies will investigate the mechanisms by which dietary micronutrients regulate macronutrient metabolism to suppress pathogen virulence to yield asymptomatic carriers of the pathogen. The proposed studies will focus on understanding how micronutrient metabolism orchestrates glucose and lipid processes in the body to suppress pathogen virulence. The proposed studies will then examine the interplay between the adaptive immune response and micronutrient mediated cooperative defenses, elucidating how these two systems cooperate to mediate healthy host-pathogen interactions and protect from infectious colitis. Finally, the proposed studies will utilize this novel host-pathogen/micronutrient system to elucidate the mechanisms that drive the evolution of pathogen attenuation towards commensalism and persistence within the microbiota. This work will contribute to a better understanding for gastrointestinal mucosal adaptive immunology, mechanisms of acute and chronic gastrointestinal inflammation and colitis, the effects of gastrointestinal microbes and microbial metabolism on gastrointestinal health and disease, including the effects of pathogenic bacterial pathogens.