Microbiota Outgrowth by Salmonella

性状（由申请方提供）：肠道沙门氏菌血清型鼠伤寒沙门氏菌（S.鼠伤寒沙门氏菌）引起胃肠炎，这是一种以急性肠道炎症为特征的肠道疾病。病原体通过使用其毒力因子侵入肠上皮并在组织巨噬细胞中存活来引发炎症。炎症伴随着管腔环境的变化，这打破了S。鼠伤寒杆菌和常驻微生物群有利于病原体。哪些机制负责微生物群组成的这些变化的问题代表了将在本申请中解决的高影响主题。我们的中心假设是炎症产生了一种新的呼吸电子受体连四硫酸盐，它促进了S.通过使病原体能够利用在肠道的厌氧环境中不能通过发酵进一步分解的化合物来抑制鼠伤寒沙门氏菌。我们将测试我们的假设的不同方面，通过确定是否去除硫化物可以防止连四硫酸盐呼吸在肠道中（目标1），在发炎的肠道生长过程中的能量趋化作用（目标2），以及是否S。鼠伤寒沙门氏菌在炎症期间利用特定的营养物（目的3）。拟议的研究将通过对控制病原体，宿主及其微生物群之间平衡的分子机制提供关键的新见解（目标2和3）以及通过科学促进新干预策略的发展（目标1），将有关胃肠炎的知识推向更高水平。因此，预计拟议工作所产生的概念性进展将对该领域产生强大和持续的影响。 公共卫生相关性： 非伤寒沙门氏菌血清型是与病毒、寄生虫或细菌相关的肠炎疾病死亡的最常见原因，也是美国食源性疾病爆发的主要原因，每年产生5亿至23亿美元的医疗费用和生产力损失。最常见的人类临床分离株是肠道沙门氏菌血清型鼠伤寒沙门氏菌（S.鼠伤寒沙门氏菌（S.肠道）。本申请中提出的研究将支持对控制病原体，宿主及其微生物群之间平衡的分子机制的开创性研究。拟议的研究将通过提供对发病机制的重要新见解和通过科学促进新干预策略的发展，将有关沙门氏菌胃肠炎的知识推向更高水平。

DESCRIPTION (provided by applicant): Salmonella enterica serotype Typhimurium (S. typhimurium) causes gastroenteritis, a diarrheal illness characterized by acute intestinal inflammation. The pathogen triggers inflammation by using its virulence factors to invade the intestinal epithelium and survive in tissue macrophages. Inflammation is accompanied by changes in the luminal environment, which tip the balance in the competition between S. typhimurium and the resident microbiota in favor of the pathogen. The question of which mechanisms are responsible for these changes in the microbiota composition represents a high-impact topic that will be addressed in this application. Our central hypothesis is that inflammation generates a new respiratory electron acceptor, tetrathionate, which promotes a luminal outgrowth of S. typhimurium by enabling the pathogen to utilize compounds that cannot be further broken down by fermentation in the anaerobic environment of the gut. We will test different aspects of our hypothesis by determining whether removal of sulfide can prevent tetrathionate respiration in the gut (Aim 1), the role of energy taxis during growth in the inflamed gut (Aim 2) and whether S. typhimurium utilizes specific nutrients during inflammation (Aim 3). The proposed research will drive knowledge about gastroenteritis to a higher level by providing critical new insights into molecular mechanisms that control the balance between the pathogen, the host and its microbiota (Aims 2 and 3) and by facilitating the development of new intervention strategies through science (Aim 1). The conceptual advances resulting from the proposed work are thus expected to have a strong and sustained influence on the field. PUBLIC HEALTH RELEVANCE: Non-typhoidal Salmonella serotypes are the single most common cause of death from diarrheal disease associated with viruses, parasites or bacteria and the leading cause of food-borne disease outbreaks in the United States, producing between $0.5 billion to $2.3 billion in annual costs for medical care and lost productivity. The most common human clinical isolates are Salmonella enterica serotypes Typhimurium (S. typhimurium) and Enteritidis (S. Enteritidis). Research proposed in this application will support pioneering studies on molecular mechanisms that control the balance between the pathogen, the host and its microbiota. The proposed studies will drive knowledge about Salmonella gastroenteritis to a higher level by providing critical new insights into pathogenesis and by facilitating the development of new intervention strategies through science.