Department of Population Medicine and Diagnostic Sciences, Cornell University, Ithaca, New York, USA.
mBio. 2023 Apr 25;14(2):e0001223. doi: 10.1128/mbio.00012-23. Epub 2023 Apr 5.
The intestine is a complex, ever-changing environment replete with an array of signaling molecules. To colonize such a complex organ, pathogens have adapted to utilize specific cues from the local environment to intricately regulate the expression of their virulence determinants. Salmonella preferentially colonizes the distal ileum, a niche enriched in the metabolite formic acid. Here, we show that the relatively higher concentration of this metabolite in the distal ileum prevents other signals from repressing Salmonella invasion in that region. We show that imported and unmetabolized formic acid functions as a cytoplasmic signal that competitively binds to HilD, the master transcriptional regulator of Salmonella invasion, thus preventing repressive fatty acids from binding to the protein. This results in an increased lifetime of HilD and subsequent derepression of invasion genes. This study demonstrates an important mechanism by which Salmonella utilizes competition among signals in the gut to its advantage as a pathogen. Enteric pathogens acutely sense their environment for signals to regulate their virulence functions. We demonstrate here that the enteric pathogen Salmonella utilizes the competition among certain regional intestinal constituents to modulate its virulence determinants in that region. We show that the high concentration of formic acid in the ileum outcompetes other signals and triggers the activation of virulence genes in the ileum. This study shows a delicate spatial and temporal mechanism by which enteric pathogens may utilize the competition among environmental cues to optimize their pathogenicity.
肠道是一个复杂且不断变化的环境，充满了一系列信号分子。为了在这样一个复杂的器官中定植，病原体已经适应了利用来自局部环境的特定线索，精细地调节其毒力决定因素的表达。沙门氏菌优先定植于回肠远端，这一部位富含代谢物甲酸。在这里，我们表明，这种代谢物在回肠远端的相对较高浓度可以防止其他信号抑制该区域的沙门氏菌入侵。我们表明，进口的和未代谢的甲酸作为细胞质信号，与沙门氏菌入侵的主转录调节剂 HilD 竞争结合，从而阻止抑制性脂肪酸与该蛋白结合。这导致 HilD 的寿命延长，随后入侵基因的去抑制。这项研究证明了沙门氏菌利用肠道中信号之间的竞争来增强其作为病原体的优势的重要机制。肠道病原体急性感知其环境中的信号，以调节其毒力功能。我们在这里证明，肠道病原体沙门氏菌利用肠道中某些区域成分之间的竞争来调节其在该区域的毒力决定因素。我们表明，回肠中甲酸的高浓度与其他信号竞争，并触发回肠中毒力基因的激活。这项研究显示了一种微妙的时空机制，肠道病原体可能利用环境线索之间的竞争来优化其致病性。
