Interspecies Bacterial Signaling to Regulate Salmonella Virulence

项目摘要 沙门氏菌感染对我国和全世界的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;抗生素很少是必要的， 并且当使用时，由于抗性菌株而经常失效。为了控制这种重要的食源性病原体， 了解它的殖民和诱发疾病的方式至关重要。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 通过降低其侵入肠上皮的能力来降低其毒力。我们建议这个信令定义了 病原菌的毒力和生长之间的良好平衡。我们发现一种新的化学物质 由γ-变形菌门的物种产生，称为扩散信号因子（DSFs）， 入侵DSFs是一种群体感应分子，我们发现它存在于小鼠的大肠中， 浓度足以抑制沙门氏菌入侵。因此，他们代表了一个新的实例， 物种信号传导和沙门氏菌疾病和携带通过其生物学调节的手段 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，并研究它们在预防疾病中的功效。我们的中央 一种假说认为，大肠中的常驻微生物群产生抑制 沙门氏菌入侵，这些信号，从而决定毒力和增长之间的平衡。我们的目标是 测试以下特定假设：1）肠道化学信号（包括DSF和其他微生物群- 衍生化合物）通过控制病原体群体的比例来调节沙门氏菌的毒力 能够入侵决定疾病和携带; 2）不同结构的信号分子结合在一个 AraC型入侵调节因子的单个结合口袋，但利用不同的结合部分，因此决定了 这些信号之间的活性和竞争; 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， 这个病原体。这里所描述的工作是重要的和创新的，因为它有可能确定一个新的 病原体控制手段不依赖于抗生素，而是针对 定殖和毒力。

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.