Mechanisms of Diet-Induced Pathogen Expansion in the Gut

项目摘要 疾病传播是一个多方面的过程，由病原体和宿主之间的相互作用介导。 肠道沙门氏菌血清型是重要的人类病原体，其引起的疾病范围从自限性 胃肠炎到持续性全身感染，如伤寒。通过粪口传播 传播途径和流行病学分析揭示了宿主传播能力的异质性。然而，在这方面， 对决定病原体脱落和传播的因素知之甚少。一些 研究描述了鼠伤寒沙门氏菌在小鼠中扩增的机制 抗生素后治疗然而，在没有抗生素的情况下，这些机制尚未被探索 治疗虽然抗生素治疗会增加人类对肠道病原体如沙门氏菌的易感性。 鼠伤寒沙门氏菌和艰难梭菌，沙门氏菌在没有抗生素治疗的情况下定植在肠道。 因此，研究S.非抗生素环境中鼠伤寒的出现和扩张 对待主人。我们利用小鼠模型研究了S.鼠伤寒扩大在 哺乳动物肠道，其中约20-30%的这些小鼠排出≥108 CFU/g粪便，并容易传播至未处理笼中 伙计们我们假设饮食的改变会影响病原体的脱落。为了验证这一点，我们 老鼠在感染时吃高胆固醇食物。我们有初步数据表明， 胆固醇饮食增加S.鼠伤寒沙门氏菌脱落水平非常迅速。这项研究的长期目标是 建议是了解如何S.鼠伤寒杆菌篡夺和操纵肠道微生物组和宿主免疫 在哺乳动物肠道定植期间的反应。在目标1中，我们将确定促进 沙门氏菌在远端肠道中的胆固醇依赖性扩张。在目标2中，我们将识别和描述 沙门氏菌的因素所需的扩展在远端肠道，并确定他们是否是特定的 在喂食高胆固醇饮食的小鼠中进行扩张。这些研究旨在更好地了解 寄主-病原体相互作用的分子机制。肠道中的鼠伤寒感染，以及 影响病原体传播。预期的结果将导致新的传输控制方法， 合理设计有益于公众健康的疗法。

PROJECT SUMMARY Disease transmission is a multifaceted process mediated by the interactions between the pathogen and host. Salmonella enterica serovars are important human pathogens that cause disease ranging from self-limiting gastroenteritis to persistent systemic infections, such as typhoid fever. Transmission occurs via the fecal-oral route, and epidemiological analyses have revealed heterogeneity in host transmission capabilities. However, relatively little is known about the factors that dictate pathogen shedding and transmission. A number of studies have described mechanisms of Salmonella enterica serovar Typhimurium expansion in mice postantibiotic treatment. However, these mechanisms have not been explored in the absence of antibiotic treatment. Although antibiotic treatment in humans enhances susceptibility to enteric pathogens such as S. Typhimurium and Clostridium difficile, Salmonella colonizes the gut in the absence of antibiotic treatment. Thus, it is important to study the mechanisms of S. Typhimurium emergence and expansion in non-antibiotic treated hosts. We use a mouse model to study molecular mechanisms of S. Typhimurium expansion in the mammalian gut in which ~20-30% of these mice shed ≥108 CFU/g feces and readily transmit to naïve cage mates. We hypothesized that alterations in the diet could influence pathogen shedding. To test this, we fed mice a high cholesterol diet at the time of infection. We have preliminary data demonstrating that high cholesterol diet increases S. Typhimurium shedding levels very rapidly. The long-term goal of this research proposal is to understand how S. Typhimurium usurps and manipulates the gut microbiome and host immune responses during colonization of the mammalian gut. In Aim 1, we will identify host factors that promote cholesterol-dependent expansion of Salmonella in the distal gut. In Aim 2, we will identify and characterize Salmonella factors required for expansion in the distal gut, and determine whether they are specific for expansion in mice fed a high cholesterol diet. These studies are aimed at gaining a better understanding of the molecular mechanisms of host-pathogen interactions during S. Typhimurium infections in the gut, and influence pathogen transmission. The expected results will lead to new methods of transmission control and to the rational design of therapeutics that will benefit public health.