Interspecies Bacterial Signaling to Regulate Salmonella Virulence

项目总结摘要 在我国和全世界，沙门氏菌感染对人类健康构成持续威胁。 然而，我们在控制沙门氏菌病方面的进展在很大程度上是徒劳的；很少有必要使用抗生素， 而且，当使用时，经常会因为耐药菌株而失败。为了控制这种重要的食源性病原体， 对于了解它的殖民和引发疾病的手段是必不可少的。分子的化学信号 肠道，包括动物宿主和微生物群产生的肠道，可以抑制沙门氏菌。 通过降低其侵袭肠道上皮的能力而产生毒力。我们认为该信令定义了 病原菌的毒力和生长之间的微妙平衡。我们发现了一类新的化学物质 由伽玛变形杆菌产生的，被称为扩散信号因子(DSFs)的物种，有效地抑制 入侵。DSFs是一种群体感应分子，我们已经发现存在于 足够的浓度来抑制沙门氏菌的入侵。因此，它们既代表了一个新的例子，也是一个 物种信号和沙门氏菌的生物学调节疾病和携带的手段 环境。这项工作的长期目标是确定抑制沙门氏菌入侵的实用方法 从而减少临床和亚临床沙门氏菌病。我们的目标是了解 侵袭抑制化合物的功能，并研究其预防疾病的效果。我们的中央 假说是，大肠中驻留的微生物群产生的化学信号抑制了 沙门氏菌入侵，这些信号因此决定了毒力和生长之间的平衡。我们的目标是 测试特定的假设：1)肠道化学信号(包括DSFs和其他微生物区系- 衍生化合物)通过控制病原菌种群比例来调节沙门氏菌的毒力 能够入侵以指示疾病和携带；2)不同结构的信号分子结合在 AraC型侵袭调节剂的单个结合口袋，但利用不同的结合部分，从而决定 这些信号之间的活性和竞争，以及；3)抑制入侵的信号可以在 使用重组细菌减少沙门氏菌病的临床症状和肠道定植的动物 这种病原体。这里描述的工作是有意义的和创新的，因为它有可能识别一部小说 一种病原体控制手段，不依赖抗生素，而是针对 殖民主义和毒力。

PROJECT SUMMARY ABSTRACT Infections by Salmonella present a constant threat to human health in our country and throughout the world. Yet, our progress toward controlling salmonellosis has been largely fruitless; antibiotics are rarely warranted, and, when used, frequently fail due to resistant strains. To control this important foodborne pathogen, it is essential to understand the means by which it colonizes and induces disease. Chemical signals of the intestine, including those produced by both the animal host and the microbiota, can repress Salmonella virulence by reducing its ability to invade the intestinal epithelium. We propose that this signaling defines the fine balance between virulence and growth of the pathogen. We have found that a novel class of chemicals produced by species of the Gammaproteobacteria, termed diffusible signal factors (DSFs), potently represses invasion. DSFs are quorum-sensing molecules that we have found to exist in the large intestine of mice in sufficient concentration to inhibit Salmonella invasion. They therefore represent both a novel instance of inter- species signaling and a means by which Salmonella disease and carriage is modulated by its biological environment. The long-term goal of this work is to identify practical means to inhibit Salmonella invasion in humans and thus to reduce clinical and sub-clinical salmonellosis. Our objectives are to understand how invasion-inhibiting compounds function, and to investigate their efficacy in preventing disease. Our central hypothesis is that the resident microbiota of the large intestine produce chemical signals that repress Salmonella invasion, and that these signals thus dictate the balance between virulence and growth. We aim to test the specific hypotheses that: 1) Intestinal chemical signals (including both DSFs and other microbiota- derived compounds) modulate Salmonella virulence by controlling the proportion of the pathogen population capable of invasion to dictate disease and carriage; 2) Signaling molecules of varying structures bind within a single binding pocket of AraC-type invasion regulators, but utilizing different binding moieties, thus dictating activity and competition among these signals, and; 3) Signals repressive for invasion can be produced in animals using recombinant bacteria to reduce both clinical signs of salmonellosis and intestinal colonization by this pathogen. The work described here is significant and innovative as it has potential to identify a novel means of pathogen control that does not rely upon antibiotics but instead targets attributes essential to colonization and virulence.