Mechanisms of Diet-Induced Pathogen Expansion in the Gut

项目总结 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所介导。 肠炎沙门氏菌血清型是人类重要的病原体，可引起各种疾病，包括自限性疾病。 胃肠炎到持续性全身感染，如伤寒。通过粪便-口腔传播 和流行病学分析显示，宿主传播能力存在异质性。然而， 关于决定病原体脱落和传播的因素，人们知之甚少。一批 已有研究描述了鼠伤寒沙门氏菌在小鼠体内的扩张机制 抗生素后治疗。然而，在缺乏抗生素的情况下，这些机制还没有被探索。 治疗。尽管人类的抗生素治疗增加了对肠道病原体的易感性，如S。 鼠伤寒沙门氏菌和艰难梭菌，沙门氏菌在缺乏抗生素治疗的情况下在肠道定植。 因此，研究鼠伤寒沙门氏菌在非抗生素中的产生和扩展机制具有重要意义。 治疗过的宿主。我们用小鼠模型研究了鼠伤寒沙门氏菌在体内的分子机制。 哺乳动物肠道，其中约20%-30%的小鼠排出≥108cfu/g粪便，并容易传播到幼稚的笼子里 伙计们。我们假设饮食的改变可能会影响病原体的脱落。为了测试这一点，我们给 老鼠在感染时会吃高胆固醇的食物。我们有初步数据表明， 高胆固醇饮食会迅速增加鼠伤寒沙门氏菌的脱落水平。这项研究的长期目标是 建议是了解鼠伤寒沙门氏菌如何篡夺和操纵肠道微生物群和宿主免疫 哺乳动物肠道定植过程中的反应。在目标1中，我们将确定促进 沙门氏菌在远端肠道中依赖胆固醇的扩张。在目标2中，我们将确定和描述 沙门氏菌因子在远端肠道中扩张所需的，并确定它们是否对 喂食高胆固醇饮食的小鼠的扩张。这些研究的目的是为了更好地了解 肠道感染鼠伤寒沙门氏菌过程中宿主-病原体相互作用的分子机制 影响病原体的传播。预期结果将导致新的传播控制方法和 合理设计有利于公众健康的治疗方法。

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.