Central metabolism of Salmonella in the inflamed gut

项目总结 感染肠道沙门氏菌血清型鼠伤寒沙门氏菌是引起 炎症性腹泻。耐人寻味的是，肠道炎症推动了S.TM种群的扩张。 肠腔。支持S.TM肠道定植的分子机制仍然存在 不完全理解。我们的中心假设是发炎的肠道构成了一种特殊的营养 使S.TM生长超过专性厌氧共生菌的环境。我们最近做了 证明在感染的急性期，中性粒细胞衍生的电子受体促进了 沙门氏菌的氧化中枢代谢。在本应用程序中，我们假设S.TM依赖于分支的TCA 最初肠道定植的周期。特别是酒石酸，通过氧化释放的微生物群产生 糖，支持分支三氯乙酸循环中富马酸的减少。我们将通过以下方式测试我们假设的关键方面 追求以下具体目标：1.确定D-酒石酸盐和L-酒石酸盐的利用对肉鸡生长的影响 S.TM在哺乳动物大肠的管腔内，2.)确定S.TM感染过程中酒石酸盐的来源， 和3.)研究体内和体外酒石酸盐利用基因的调控。这项工作将推动我们的 了解肠道病原体，如S.TM，如何使其碳和能量代谢适应 在哺乳动物肠道中定居。我们设想，通过更好地理解 美国TM在炎症过程中超过竞争对手的微生物将有助于开发新的和创新的 治疗方法。

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. We have recently demonstrated that during the acute phase of the infection, neutrophil-derived electron acceptors facilitate an oxidative central metabolism in S. Tm. In this application, we hypothesize that S. Tm relies on a branched TCA cycle for initial gut colonization. In particular, tartaric acid, produced through oxidation of microbiota-liberated sugars, supports fumarate reduction in the branched TCA cycle. We will test key aspects of our hypothesis by pursuing the following specific aims: 1.) determine how utilization of D- and L-tartrate contributes to growth of S. Tm in the lumen of the mammalian large intestine, 2.) determine the origin of tartrate during S. Tm infection, and 3.) investigate the regulation of tartrate utilization genes in vitro and in vivo. 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. We envision that a better understanding of the mechanisms by which S. Tm outgrows competing microbes during inflammation will aid the development of new and innovative approaches for treatment.