Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908.
Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908
Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14210-14215. doi: 10.1073/pnas.1902725116. Epub 2019 Jun 24.
To establish infection, enteric pathogens integrate environmental cues to navigate the gastrointestinal tract (GIT) and precisely control expression of virulence determinants. During passage through the GIT, pathogens encounter relatively high levels of oxygen in the small intestine before transit to the oxygen-limited environment of the colon. However, how bacterial pathogens sense oxygen availability and coordinate expression of virulence traits is not resolved. Here, we demonstrate that enterohemorrhagic O157:H7 (EHEC) regulates virulence via the oxygen-responsive small RNA DicF. Under oxygen-limited conditions, DicF enhances global expression of the EHEC type three secretion system, which is a key virulence factor required for host colonization, through the transcriptional activator PchA. Mechanistically, the coding sequence (CDS) base pairs with the 5' untranslated region of the mRNA to sequester the ribosome binding site (RBS) and inhibit translation. DicF disrupts -interactions by binding to the CDS, thereby unmasking the RBS and promoting PchA expression. These findings uncover a feed-forward regulatory pathway that involves distinctive mechanisms of RNA-based regulation and that provides spatiotemporal control of EHEC virulence.
为了建立感染，肠道病原体整合环境线索来导航胃肠道（GIT），并精确控制毒力决定因素的表达。在通过 GIT 时，病原体在转移到结肠缺氧环境之前，在小肠中遇到相对较高水平的氧气。然而，细菌病原体如何感知氧气可用性以及协调毒力特征的表达尚未解决。在这里，我们证明肠出血性 0157:H7（EHEC）通过氧气响应性小 RNA DicF 调节毒力。在缺氧条件下，DicF 通过转录激活因子 PchA 增强 EHEC 型三型分泌系统的全局表达，该系统是宿主定植所必需的关键毒力因子。在机制上，编码序列（CDS）与 mRNA 的 5'非翻译区碱基配对，以隔离核糖体结合位点（RBS）并抑制翻译。DicF 通过结合 CDS 破坏 -相互作用，从而暴露 RBS 并促进 PchA 表达。这些发现揭示了一个涉及基于 RNA 的调节的独特机制的正反馈调节途径，为 EHEC 毒力提供了时空控制。
