Riboflavin is produced by most commensal bacteria in the human colon, where enterohemorrhagic Escherichia coli (EHEC) colonizes and causes diseases. Sensing environmental signals to site-specifically express the type-III secretion system (T3SS), which injects effectors into host cells leading to intestinal colonization and disease, is key to the pathogenesis of EHEC. Here, we reveal that EHEC O157:H7, a dominant EHEC serotype frequently associated with severe diseases, acquired a previously uncharacterized two-component regulatory system rbfSR , which senses microbiota-produced riboflavin to directly activate the expression of LEE genes encoding the T3SS in the colon. rbfSR is present in O157:H7 and O145:H28 but absent from other EHEC serotypes. The binding site of RbfR through which it regulates LEE gene expression was identified and is conserved in all EHEC serotypes and Citrobacter rodentium , a surrogate for EHEC in mice. Introducing rbfSR into C. rodentium enabled bacteria to sense microbiota-produced riboflavin in the mouse colon to increase the expression of LEE genes, causing increased disease severity in mice. Phylogenic analysis showed that the O55:H7 ancestor of O157:H7 obtained rbfSR which has been kept in O157:H7 since then. Thus, acquiring rbfSR represents an essential step in the evolution of the highly pathogenic O157:H7. The expression of LEE genes and cell attachment ability of other EHEC serotypes in the presence of riboflavin significantly increased when rbfSR was introduced into them, indicating that those serotypes are ready to use RbfSR to increase their pathogenicity. This may present a potential public health issue as horizontal gene transfer is frequent in enteric bacteria.

中文翻译：

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大肠杆菌 O157:H7 感知微生物群产生的核黄素以增加其在肠道中的毒力

核黄素由人类结肠中的大多数共生细菌产生，肠出血的地方大肠杆菌(EHEC) 定殖并引起疾病。感知环境信号以位点特异性表达 III 型分泌系统 (T3SS)，该系统将效应物注入宿主细胞，导致肠道定植和疾病，是 EHEC 发病机制的关键。在这里，我们揭示了 EHEC O157:H7，一种经常与严重疾病相关的显性 EHEC 血清型，获得了以前未表征的双组分调节系统rbfSR，它感知微生物群产生的核黄素，直接激活编码结肠中 T3SS 的 LEE 基因的表达。rbfSR存在于 O157:H7 和 O145:H28 中，但不存在于其他 EHEC 血清型中。鉴定了 RbfR 调节 LEE 基因表达的结合位点，并且在所有 EHEC 血清型和柠檬酸杆菌，小鼠 EHEC 的替代品。介绍rbfSR进入啮齿动物使细菌能够感知小鼠结肠中微生物群产生的核黄素，从而增加 LEE 基因的表达，从而导致小鼠疾病严重程度增加。系统发育分析表明，O157:H7 的 O55:H7 祖先获得rbfSR从那以后一直保存在 O157:H7 中。因此，获得rbfSR代表了高致病性 O157:H7 进化过程中的一个重要步骤。当核黄素存在时，LEE 基因的表达和其他 EHEC 血清型的细胞粘附能力显着增加rbfSR被引入其中，表明这些血清型已准备好使用 RbfSR 来增加其致病性。这可能会带来潜在的公共卫生问题，因为水平基因转移在肠道细菌中很常见。