Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
mBio. 2022 Aug 30;13(4):e0193922. doi: 10.1128/mbio.01939-22. Epub 2022 Aug 2.
Enteric pathogens such as enterohemorrhagic E. coli (EHEC) and its surrogate murine model Citrobacter rodentium sense indole levels within the gut to navigate its biogeography and modulate virulence gene expression. Indole is a microbiota-derived signal that is more abundant in the intestinal lumen, with its concentration decreasing at the epithelial lining where it is absorbed. E. coli, but not C. rodentium, produces endogenous indole because it harbors the gene. Microbiota-derived exogenous indole is sensed by the CpxAR two-component system, where CpxA is a membrane-bound histidine-sensor-kinase (HK) and CpxR is a response regulator (RR). Indole inhibits CpxAR function leading to decreased expression of the locus of enterocyte effacement (LEE) pathogenicity island, which is essential for these pathogens to form lesions on enterocytes. In our transcriptome studies comparing wild-type (WT) EHEC and Δ ± indole, one of the most upregulated genes by indole is , which is a predicted orphan RR. Because of the role YgeV plays in the indole signaling cascade, we renamed this gene indole sensing regulator (). In the absence of endogenous indole, IsrR activates LEE gene expression. IsrR only responds to endogenous indole, with exogenous indole still blocking virulence gene expression independently from IsrR. Notably, a C. rodentium mutant is attenuated for murine infection, depicting delayed death, lower intestinal colonization, and LEE gene expression. IsrR aids in discriminating between microbiota-derived (exogenous) and endogenous self-produced indole in fine-tuning virulence gene expression by enteric pathogens in the intestine. Enteric pathogens sense the complex intestinal chemistry to find a suitable colonization niche. The microbiota plays an important part in shaping this chemistry. Here we show that the abundant microbiota-derived exogenous signal indole impacts host-pathogen interactions by allowing enteric pathogens to discriminate between the luminal environment, where expression of virulence genes is an unnecessary energy burden, from the epithelial surface, where this gene expression is needed for host colonization. We describe a new signaling node through the regulator IsrR that allows for this shift. These findings establish a mechanism through which pathogens discriminate from self- and microbiota-derived signaling to establish infection.
肠致病性病原体，如肠出血性大肠杆菌（EHEC）及其替代的鼠源模型柠檬酸杆菌属啮齿动物，可感知肠道内吲哚水平，从而导航其生物地理学并调节毒力基因表达。吲哚是一种源自微生物群的信号，在肠道腔中更为丰富，其浓度在吸收部位的上皮衬里处降低。E. coli 而不是 C. rodentium 会产生内源性吲哚，因为它含有 基因。微生物群衍生的外源性吲哚被 CpxAR 双组分系统感知，其中 CpxA 是一种膜结合组氨酸感应激酶（HK），而 CpxR 是一种应答调节子（RR）。吲哚抑制 CpxAR 功能，导致上皮细胞 effacement （LEE）致病岛的表达减少，这对于这些病原体在肠上皮细胞上形成病变是必不可少的。在我们比较野生型（WT）EHEC 和 Δ ±吲哚的转录组研究中，吲哚上调最明显的基因之一是 ，它是一个预测的孤儿 RR。由于 YgeV 在吲哚信号级联中的作用，我们将该基因重新命名为吲哚感应调节子（）。在没有内源性吲哚的情况下，IsrR 激活 LEE 基因表达。IsrR 仅对内源性吲哚有反应，而外源性吲哚仍能独立于 IsrR 阻断毒力基因表达。值得注意的是，C. rodentium 突变体在小鼠感染中减弱，表现为死亡延迟、肠道定植减少和 LEE 基因表达降低。IsrR 有助于区分肠道病原体（外源性）和内源性自身产生的吲哚，从而精细调节肠道病原体的毒力基因表达。肠致病性病原体感知复杂的肠道化学物质，以找到合适的定植小生境。微生物群在塑造这种化学物质方面起着重要作用。在这里，我们表明，丰富的微生物群衍生的外源性信号吲哚通过允许肠致病性病原体区分腔环境（其中毒力基因表达是不必要的能量负担）和上皮表面（其中这种基因表达是宿主定植所必需的），从而影响宿主-病原体相互作用。我们描述了一个通过调节剂 IsrR 实现这一转变的新信号节点。这些发现建立了一种机制，通过该机制，病原体可以区分自身和微生物群衍生的信号以建立感染。
