Glutarate metabolism in Salmonella

项目摘要 感染细菌病原体肠道沙门氏菌血清型鼠伤寒沙门氏菌（S。Tm） 是炎症性腹泻的常见原因。有趣的是，肠道炎症 S.肠腔中的Tm群体。的分子机制 支持S. Tm在肠道的定植仍不完全清楚。我们 核心假设是发炎的肠道构成了一个特殊的营养环境 使S. TM的生长速度超过专性厌氧共生细菌。在这 应用，我们将研究炎症反应性氧和氮物种 正在产生一系列与炎症相关的小代谢物。我们 假设活性氧和氮物质将糖氧化成较小的单- 和二羧酸如戊二酸，它们是S. TM支持 肠道殖民我们将在小鼠感染模型中测试我们假设的关键方面 和体外培养。我们会致力达致以下的具体目标：（1）确定戊二酸盐是否 和其它羧酸作为RNS代谢的副产物产生，和2. 调查S.戊二酸在感染中的代谢。这项工作将推进 我们对肠道病原体，如沙门氏菌，Tm，调整它们的碳， 通过能量代谢在哺乳动物的肠道中定居。这些研究也 有望推进我们对活性氧和氮物质 参与形成代谢物景观的多样性生成反应， 肠道炎症

PROJECT SUMMARY Infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Tm) is a common cause of inflammatory diarrhea. Intriguingly, intestinal inflammation drives an expansion of the S. Tm population in the gut lumen. The molecular mechanisms that support S. Tm colonization of the intestinal tract remain incompletely understood. Our central hypothesis is that the inflamed gut constitutes a peculiar nutritional environment that enables S. Tm to outgrow obligate anaerobic commensal bacteria. In this application, we will investigate how inflammatory reactive oxygen and nitrogen species are generating a diverse array of inflammation-associated small metabolites. We hypothesize that reactive oxygen and nitrogen species oxidize sugars to smaller mono- and dicarboxylic acids such as glutarate, which serve as nutrients for S. Tm to support gut colonization. We will test key aspects of our hypothesis in mouse models of infection and in vitro. We will pursue the following specific aims: 1.) Determine whether glutarate and other carboxylic acids are generated as byproducts of RNS metabolism, and 2. Investigate S. Tm glutarate metabolism in the context of infection. This work will advance our understanding of how intestinal pathogens, such as S. Tm, adapt their carbon and energy metabolism to colonize the mammalian intestinal tract. These studies are also expected to advance our understanding of how reactive oxygen and nitrogen species participate in diversity-generating reactions that shape the metabolite landscape during gut inflammation.