肠道病原体如肠沙门氏菌在整个感染过程中经历代谢景观的时空变化。宿主活性氧和氮类非酶促将单糖转化为α-羟基酸,包括L-酒石酸盐.沙门氏菌在感染早期利用L-酒石酸盐支持富马酸盐呼吸,而L-酒石酸盐的利用在稍后的时间点停止,由于外源电子受体如四硫酸盐的可用性增加,硝酸盐,和氧气。沙门氏菌如何调节其基因表达以代谢适应不断变化的营养环境仍然未知。这里,我们研究了沙门氏菌中L-酒石酸代谢的转录调控如何受到感染相关线索的影响。L-酒石酸盐诱导ttdBAU的转录,参与L-酒石酸盐利用的基因。L-酒石酸盐代谢由两个先前未表征的转录调节因子TtdV(STM3357)和TtdW(STM3358)负调节,并且TtdV和TtdW都需要用于L-酒石酸盐的感测。电子受体硝酸盐,四硫酸盐,氧通过双组分系统ArcAB抑制ttdBAU转录。此外,在沙门氏菌诱导的结肠炎小鼠模型中,L-酒石酸盐代谢的调节是最佳适应性所必需的。TtdV,TtdW,和ArcAB允许两个线索的整合,即,底物可用性和外源电子受体的可用性,控制L-酒石酸盐代谢。我们的发现为沙门氏菌如何优先利用不同的电子受体进行呼吸提供了新的见解,因为它在整个感染过程中经历了过渡的营养可用性。
目的:细菌病原体必须调整其基因表达谱,以应对感染过程中遇到的各种环境。这种协调过程是通过整合病原体感知的线索来进行的,以时空方式微调基因表达。许多研究已经阐明了沙门氏菌如何感知肠道中的代谢物以激活或抑制其毒力程序的调节机制;然而,我们对沙门氏菌如何协调其基因表达以最大限度地利用过渡性营养生态位中的碳和能源的理解还没有很好地理解。在这项研究中,我们发现了沙门氏菌如何整合两个与感染相关的线索,底物可用性和外源电子受体,控制L-酒石酸盐代谢。从我们的实验来看,除了表征两个先前未知的转录调节因子外,我们还提出了一个模型,用于如何响应不同的代谢线索来调节L-酒石酸盐的代谢。这项研究扩展了我们对微生物如何结合代谢线索以增强感染期间的适应性的理解。
Enteric pathogens such as Salmonella enterica serovar Typhimurium experience spatial and temporal changes to the metabolic landscape throughout infection. Host reactive oxygen and nitrogen species non-enzymatically convert monosaccharides to alpha hydroxy acids, including L-tartrate. Salmonella utilizes L-tartrate early during infection to support fumarate respiration, while L-tartrate utilization ceases at later time points due to the increased availability of exogenous electron acceptors such as tetrathionate, nitrate, and oxygen. It remains unknown how Salmonella regulates its gene expression to metabolically adapt to changing nutritional environments. Here, we investigated how the transcriptional regulation for L-tartrate metabolism in Salmonella is influenced by infection-relevant cues. L-tartrate induces the transcription of ttdBAU, genes involved in L-tartrate utilization. L-tartrate metabolism is negatively regulated by two previously uncharacterized transcriptional regulators TtdV (STM3357) and TtdW (STM3358), and both TtdV and TtdW are required for the sensing of L-tartrate. The electron acceptors nitrate, tetrathionate, and oxygen repress ttdBAU transcription via the two-component system ArcAB. Furthermore, the regulation of L-tartrate metabolism is required for optimal fitness in a mouse model of Salmonella-induced colitis. TtdV, TtdW, and ArcAB allow for the integration of two cues, i.e., substrate availability and availability of exogenous electron acceptors, to control L-tartrate metabolism. Our findings provide novel insights into how Salmonella prioritizes the utilization of different electron acceptors for respiration as it experiences transitional nutrient availability throughout infection.
OBJECTIVE: Bacterial pathogens must adapt their gene expression profiles to cope with diverse environments encountered during infection. This coordinated process is carried out by the integration of cues that the pathogen senses to fine-tune gene expression in a spatiotemporal manner. Many studies have elucidated the regulatory mechanisms of how Salmonella sense metabolites in the gut to activate or repress its virulence program; however, our understanding of how Salmonella coordinates its gene expression to maximize the utilization of carbon and energy sources found in transitional nutrient niches is not well understood. In this study, we discovered how Salmonella integrates two infection-relevant cues, substrate availability and exogenous electron acceptors, to control L-tartrate metabolism. From our experiments, we propose a model for how L-tartrate metabolism is regulated in response to different metabolic cues in addition to characterizing two previously unknown transcriptional regulators. This study expands our understanding of how microbes combine metabolic cues to enhance fitness during infection.