The role of redox sensing in Listeria monocytogenes pathogenesis

项目总结 单核细胞增多性李斯特氏菌致病机制中一个被严重忽视的部分是哺乳动物的定植 胆囊炎。胆囊是几种肠道病原体的主要细菌储存库，包括LM， 沙门氏菌和弯曲杆菌，并作为粪便分泌菌的来源，具有潜在的 增加这些食源性病原体的传播。在这里，我们将剖析 并确定对胆囊虫定植至关重要的细菌代谢和应激反应途径 小鼠的胆汁。为此，我们提供了我们新的体外模型的初步数据。 使用非人类灵长类动物的器官进行殖民(NHP)。这些结果为调查奠定了基础 转化为胆囊腔内LM复制所必需的特定基因和途径。这样做的目的是 该提案将以三个具体目标完成：(1)将胆囊定义为LM的复制利基。 为此，我们将确定LM在胆囊中的定位，并定义在 胆囊腔。(2)确定胆囊壁定植所需的LM基因。给你，荧光粉 将对报告菌株进行改造，以确定在胆囊中激活的LM信号通路 在感染期间。此外，我们将评估特定的LM基因和途径在发病机制中的作用， 重点放在胆道定植上。(3)确定免疫应答在∆雷克斯感染中的作用。 我们的方法是技术创新的，因为它利用了我们新的NHP胆囊定植模型 在全球范围内评估对在这一独特的利基环境中复制至关重要的细菌基因。这些研究的结果将 意义重大，因为他们将发现细菌病原体如何在胆囊中复制，并有可能 发现治疗目标，以减少肠道病原体的定植和传播。

PROJECT SUMMARY A critically understudied part of Listeria monocytogenes (Lm) pathogenesis is colonization of the mammalian gallbladder. The gallbladder is the primary bacterial reservoir for several enteric pathogens, including Lm, Salmonella, and Campylobacter, and serves as the source of fecally secreted bacteria that has the potential to increase transmission of these foodborne pathogens. Here, we will dissect the nature of Lm growth in the gallbladder and identify the bacterial metabolic and stress response pathways critical for colonization of the murine gallbladder. To that end, we present preliminary data from our novel ex vivo model of Lm gallbladder colonization using organs from non-human primates (NHP). These results have set the stage for investigations into specific genes and pathways necessary for Lm replication in the gallbladder lumen. The objectives of this proposal will be accomplished with three Specific Aims: (1) Define the gallbladder as a replicative niche for Lm. To do this, we will determine the localization of Lm in the gallbladder and define the metabolites available in the gallbladder lumen. (2) Identify the Lm genes required for colonization of the gallbladder. Here, fluorescent reporter strains will be engineered to identify the Lm signaling pathways that are activated in the gallbladder during infection. Additionally, we will evaluate specific Lm genes and pathways for their roles in pathogenesis, with a focus on gallbladder colonization. (3) Determine the role of the immune response to Lm ∆rex infection. Our approach is technically innovative as it takes advantage of our novel model of NHP gallbladder colonization to globally assess bacterial genes important for replication in this unique niche. Results from these studies will be significant as they will uncover how bacterial pathogens replicate in the gallbladder and have the potential to uncover therapeutic targets to reduce colonization and spread of enteric pathogens.