Microbial Metabolites Inhibiting Salmonella Carriage and Disease

摘要 扩散信号因子（DSFs），具有特征性顺式-2不饱和的长链脂肪酸， 并被几种革兰氏阴性细菌用作群体感应信号。我们发现 DSF cis-2 hexadecenoic acid（c2-HDA）在抑制沙门氏菌功能的表达方面是非常有效的 并且已经发现该化合物存在于小鼠大肠杆菌中。 肠。由于没有描述具有2-顺式不饱和的脂肪酸的哺乳动物来源，因此，这些 研究结果强烈表明，肠道微生物群的成分产生和分泌抑制 沙门氏菌毒力。我们假设沙门氏菌利用这些细菌的信号来平衡其 毒力功能，对入侵细菌的适应性和生存至关重要，但也是昂贵的， 沙门氏菌群体的定殖和增殖。因此，肠道微生物代谢产物可能 病原体的多重协调目的，平衡毒力功能与增殖所需功能 从而通过多种方式影响病原体在肠道中的存活。在此，我们建议：目标1： 使用互补方法鉴定产生抑制性DSFs的人类肠道微生物组细菌 目的2：确定DSFs在沙门氏菌中调控的功能群 并鉴定这种控制的机制;目的3：使用建立的沙门氏菌感染的鼠模型， 描述c2-HDA的生物学功能和翻译相关性，以了解其作用机制。 行动，并支持最终开发新的治疗方法，如活生物制品， 人类沙门氏菌病的控制。

ABSTRACT Diffusible signal factors (DSFs), long-chain fatty acids with a characteristic cis-2 unsaturation, are produced and used by several genera of gram-negative bacteria as quorum-sensing signals. We have found that the DSF cis-2 hexadecenoic acid (c2-HDA) is extremely potent in inhibiting expression of Salmonella functions necessary for colonization of the intestine and have found this compound to be present in the murine large intestine. As no mammalian source of fatty acids harboring a 2-cis unsaturation has been described, these findings strongly suggest that constituents of the gut microbiota produce and excrete DSFs that inhibit Salmonella virulence. We hypothesize that Salmonella uses the signals of these bacteria to balance its virulence functions, essential but also costly to the fitness and survival of the invading bacteria, with colonization and proliferation of the Salmonella population. Gut microbial metabolites may therefore serve multiple coordinated purposes in pathogens, balancing virulence functions with those required for proliferation within a host and thus affecting pathogen survival in the gut by multiple means. Here we propose to: Aim 1: Use complementary approaches to identify bacteria of the human gut microbiome that produce inhibitory DSFs and characterize their products; Aim 2: Identify the constellation of functions regulated in Salmonella by DSFs and identify mechanisms of this control, and; Aim 3: Using established murine models of Salmonella infection, characterize the biological function and translational relevance of c2-HDA to understand its mechanism of action and to support the eventual development of novel therapeutics, such as live biotherapeutic products, for the control of human salmonellosis.