Department of Internal Medicine, Division of Infectious Diseases, UC Davis School of Medicine, Davis, California, USA.
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
mBio. 2024 Jun 12;15(6):e0035024. doi: 10.1128/mbio.00350-24. Epub 2024 Apr 29.
Enteric pathogens such as 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. 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 regulates its gene expression to metabolically adapt to changing nutritional environments. Here, we investigated how the transcriptional regulation for L-tartrate metabolism in is influenced by infection-relevant cues. L-tartrate induces the transcription of , 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 transcription via the two-component system ArcAB. Furthermore, the regulation of L-tartrate metabolism is required for optimal fitness in a mouse model of -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 prioritizes the utilization of different electron acceptors for respiration as it experiences transitional nutrient availability throughout infection.
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 sense metabolites in the gut to activate or repress its virulence program; however, our understanding of how 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 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.
肠病原体，如鼠伤寒血清型，在感染过程中经历代谢景观的时空变化。宿主活性氧和氮物种非酶地将单糖转化为α-羟基酸，包括 L-酒石酸。在感染早期利用 L-酒石酸来支持延胡索酸盐呼吸，而随着四硫代硝酸盐、硝酸盐和氧气等外源电子受体的可用性增加，L-酒石酸的利用在后期停止。目前尚不清楚 如何调节其基因表达以适应不断变化的营养环境。在这里，我们研究了感染相关线索如何影响 中 L-酒石酸代谢的转录调控。L-酒石酸诱导 基因的转录，这些基因参与 L-酒石酸的利用。L-酒石酸代谢受到两个以前未被表征的转录调节因子 TtdV（STM3357）和 TtdW（STM3358）的负调控，并且 TtdV 和 TtdW 都需要感应 L-酒石酸。电子受体硝酸盐、四硫代硝酸盐和氧气通过双组分系统 ArcAB 抑制 转录。此外，L-酒石酸代谢的调节对于 -诱导的结肠炎小鼠模型中的最佳适应性至关重要。TtdV、TtdW 和 ArcAB 允许整合两个线索，即底物可用性和外源电子受体的可用性，以控制 L-酒石酸代谢。我们的发现为 如何在感染过程中经历过渡营养可用性时优先利用不同电子受体进行呼吸提供了新的见解。
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。这个协调的过程是通过整合病原体感知的线索来完成的，这些线索以时空方式精细地调节基因表达。许多研究已经阐明了 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 如何协调其基因表达以最大限度地利用过渡营养小生境中发现的碳和能源来源的理解还不是很清楚。在这项研究中，我们发现了 如何整合两个感染相关的线索，即底物可用性和外源电子受体，以控制 L-酒石酸代谢。通过我们的实验，我们提出了一个模型，说明 L-酒石酸代谢如何响应不同的代谢线索进行调节，同时还描述了两个以前未知的转录调节因子。这项研究扩展了我们对微生物如何结合代谢线索在感染过程中增强适应性的理解。
