Virulence meets metabolism: Cra and KdpE gene regulation in enterohemorrhagic Escherichia coli.
Virulence meets metabolism: Cra and KdpE gene regulation in enterohemorrhagic Escherichia coli.
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DOI：
10.1128/mbio.00280-12
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发表时间：
2012-10-16
期刊：
影响因子：
6.4
通讯作者：
Sperandio V
中科院分区：
文献类型：
--
作者：
Njoroge JW;Nguyen Y;Curtis MM;Moreira CG;Sperandio V
胃肠道（GI）细菌感知不同的环境信号，作为差异基因调控和生态位适应的线索。引起血性腹泻的肠出血性大肠杆菌 (EHEC) 等病原体利用这些信号对其毒力因子进行时间和能量有效的调节。 EHEC 采用的主要毒力策略之一是在肠细胞上形成附着和擦除 (AE) 损伤。形成这些病变所需的大多数基因都集中在一个致病岛内，即肠细胞消失位点（LEE），其表达需要 LEE 编码的调节因子 Ler。在这里，我们表明，EHEC 在糖酵解环境中的生长会抑制 ler 的表达，从而抑制所有其他 LEE 基因的表达。相反，糖异生环境中的生长激活这些基因的表达。这种糖依赖性调节是通过两个转录因子实现的：KdpE 和 Cra。 Cra 和 KdpE 都直接与 ler 启动子结合，并且 Cra 对该启动子的亲和力是分解代谢物依赖性的。此外，我们发现 Cra 和 KdpE 蛋白在体外相互作用，并且 Cra 的存在增强了 KdpE 结合 DNA 的能力。 Cra 对于 AE 病变形成很重要，KdpE 有助于这种 Cra 依赖性调节。 cra 和 kdpE 的缺失导致 AE 病变的消融。胃肠道内细菌面临的众多挑战之一是成功竞争碳源。将碳代谢与毒力表达的精确协调联系起来是病原体适应胃肠道环境的关键步骤。对环境信号做出适当而迅速的反应对于细菌的生存至关重要。 Cra 和 KdpE 是在非致病性和致病性细菌中发现的两种蛋白质，它们根据代谢物浓度的差异调节基因。在这项工作中，我们表明，在导致血性腹泻的致命病原体肠出血性大肠杆菌 (EHEC) O157:H7 中，这两种蛋白质影响重要的毒力特征。我们还提出，它们对这些毒力特征中的一种或多种的控制是由于 Cra 和 KdpE 蛋白彼此之间以及与它们的 DNA 靶标的直接相互作用。这项工作展示了肠出血性大肠杆菌如何利用已建立的机制来感知环境中的代谢物和应激线索，以时间和能量有效的方式诱导毒力因子，最终导致疾病。了解病原体如何侵占非致病系统可以帮助我们制定控制措施。
Gastrointestinal (GI) bacteria sense diverse environmental signals as cues for differential gene regulation and niche adaptation. Pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, use these signals for the temporal and energy-efficient regulation of their virulence factors. One of the main virulence strategies employed by EHEC is the formation of attaching and effacing (AE) lesions on enterocytes. Most of the genes necessary for the formation of these lesions are grouped within a pathogenicity island, the locus of enterocyte effacement (LEE), whose expression requires the LEE-encoded regulator Ler. Here we show that growth of EHEC in glycolytic environments inhibits the expression of ler and consequently all other LEE genes. Conversely, growth within a gluconeogenic environment activates expression of these genes. This sugar-dependent regulation is achieved through two transcription factors: KdpE and Cra. Both Cra and KdpE directly bind to the ler promoter, and Cra’s affinity to this promoter is catabolite dependent. Moreover, we show that the Cra and KdpE proteins interact in vitro and that KdpE’s ability to bind DNA is enhanced by the presence of Cra. Cra is important for AE lesion formation, and KdpE contributes to this Cra-dependent regulation. The deletion of cra and kdpE resulted in the ablation of AE lesions. One of the many challenges that bacteria face within the GI tract is to successfully compete for carbon sources. Linking carbon metabolism to the precise coordination of virulence expression is a key step in the adaptation of pathogens to the GI environment. An appropriate and prompt response to environmental cues is crucial for bacterial survival. Cra and KdpE are two proteins found in both nonpathogenic and pathogenic bacteria that regulate genes in response to differences in metabolite concentration. In this work, we show that, in the deadly pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7, which causes bloody diarrhea, these two proteins influence important virulence traits. We also propose that their control of one or more of these virulence traits is due to the direct interaction of the Cra and KdpE proteins with each other, as well as with their DNA targets. This work shows how EHEC coopts established mechanisms for sensing the metabolites and stress cues in the environment, to induce virulence factors in a temporal and energy-efficient manner, culminating in disease. Understanding how pathogens commandeer nonpathogenic systems can help us develop measures to control them.