The role of redox sensing in Listeria monocytogenes pathogenesis

氧化还原传感在单核细胞增生李斯特菌发病机制中的作用

• 批准号: 10580557
• 负责人: Michelle Lynne Reniere
• 金额: $ 50.78万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580557
• 关键词: Adult; Attenuated; Bacteria; Bacterial Genes; Bacterial Infections; Biochemical; Campylobacter; Cells; Columnar Epithelium; Critical Pathways; Data; Disease; Engineering; Environment; Epithelial; Epithelial Cells; Exhibits; Flow Cytometry; Fractionation; Gallbladder; Gastrointestinal tract structure; Genes; Growth; Histology; Immune; Immune response; Immunohistochemistry; Infection; Interferons; Intestines; Invaded; Investigation; Listeria monocytogenes; Liver; Metabolic; Metabolic Pathway; Metabolic stress; Modeling; Molecular; Morbidity - disease rate; Mucous body substance; Mus; Nature; Nutrient; Oral; Organ; Oxidation-Reduction; Pathogenesis; Pathway interactions; Pattern; Persons; Proliferating; Regulation; Reporter; Role; Salmonella; Salmonella typhi; Signal Pathway; Source; Spleen; Testing; Time; Tissues; Virulence; biological adaptation to stress; enteric infection; enteric pathogen; experimental study; extracellular; foodborne pathogen; immune clearance; in vivo; innate immune pathways; innovation; insight; mortality; mouse model; mutant; new therapeutic target; nonhuman primate; novel; pathogen; pathogenic bacteria; stressor; therapeutic target; transmission process; transposon sequencing

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.

项目概要 单核细胞增生李斯特菌 (Lm) 发病机制中一个未被充分研究的部分是哺乳动物的定植 胆囊。胆囊是多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，是粪便分泌细菌的来源，有可能 增加这些食源性病原体的传播。在这里，我们将剖析 Lm 增长的本质 胆囊并确定对胆囊定植至关重要的细菌代谢和应激反应途径 小鼠胆囊。为此，我们提供了来自 Lm 胆囊的新型离体模型的初步数据 使用非人类灵长类动物（NHP）的器官进行定殖。这些结果为调查奠定了基础 进入胆囊腔内 Lm 复制所需的特定基因和途径。本次活动的目标 该提案将通过三个具体目标来完成：（1）将胆囊定义为 Lm 的复制生态位。 为此，我们将确定 Lm 在胆囊中的定位并定义胆囊中可用的代谢物 胆囊腔。 (2)鉴定胆囊定植所需的Lm基因。这里，荧光 报告菌株将被设计来识别胆囊中激活的 Lm 信号通路 感染期间。此外，我们将评估特定的 Lm 基因和通路在发病机制中的作用， 重点关注胆囊定植。 (3) 确定免疫反应对 Lm Δrex 感染的作用。 我们的方法在技术上是创新的，因为它利用了我们的新型 NHP 胆囊定植模型 全面评估在这个独特的生态位中对于复制重要的细菌基因。这些研究的结果将 意义重大，因为它们将揭示细菌病原体如何在胆囊中复制，并有可能 发现减少肠道病原体定植和传播的治疗靶点。