PDF(Pubmed)
Abstract：
The enteric pathogens have evolved to utilize elements from their surroundings to optimize their infection strategies. A common mechanism to achieve this is to employ intestinal compounds as signals to control the activity of a master regulator of virulence. Shigella flexneri (S. flexneri) is a highly infectious entero-invasive pathogen which requires very few organisms to cause invasion of the colonic mucosa. The invasion program is controlled by the virulence master regulator VirF. Here, we show that the fatty acids commonly found in the colon can be exploited by S. flexneri to repress its virulence, allowing it to energetically finance its proliferation, thus increasing its pathogenicity. Colonic fatty acids such as oleic, palmitoleic and cis-2-hexadecenoic acid were shown to directly bind to VirF and mediate its prompt degradation. These fatty acids also disrupted the ability of VirF to bind to its target DNA, suppressing the transcription of the downstream virulence genes and significantly reducing the invasion of S. flexneri to colonic epithelial cells. Treatment with colonic fatty acids significantly increased the growth rate of the pathogen only under invasion-inducing conditions, showing that the reduction in the burden of virulence promotes a growth advantage. These results demonstrate the process by which S. flexneri can employ intestinal compounds as signals to increase its numbers at its preferred site of invasion, highlighting the mechanism by which the full spectrum of shigellosis is achieved despite a miniscule infectious dose. This highlights an elegant model of environmental adaption by S. flexneri to maximize the pathogenic benefit.
摘要：
肠道病原体已经进化为利用其周围环境的元素来优化其感染策略。实现这一点的常见机制是使用肠化合物作为信号来控制毒力的主调节剂的活性。福氏志贺氏菌(S.flexneri）是一种高度传染性的肠道入侵病原体，需要很少的生物来引起结肠粘膜的入侵。入侵程序由毒力主调节因子VirF控制。这里,我们表明，在结肠中常见的脂肪酸可以被福氏杆菌利用来抑制其毒力，允许它积极资助其扩散，从而增加其致病性。结肠脂肪酸，如油酸，棕榈油酸和顺式-2-十六碳烯酸被证明直接与VirF结合并介导其迅速降解。这些脂肪酸还破坏了VirF与其靶DNA结合的能力，抑制下游毒力基因的转录，并显着降低福氏链球菌对结肠上皮细胞的侵袭。只有在诱导入侵的条件下，用结肠脂肪酸处理才能显着增加病原体的生长速率。表明毒力负担的减少促进了增长优势。这些结果证明了福氏杆菌可以使用肠道化合物作为信号以增加其在其首选入侵部位的数量的过程。强调了尽管感染剂量很小，但仍可实现志贺氏菌病全谱的机制。这突出了弗氏链球菌环境适应的优雅模型，以最大限度地提高致病效益。
