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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

基本信息

批准号：
10708923
负责人：
Michelle Lynne Reniere
金额：
$ 52.94万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10708923
关键词：
Adult Attenuated Bacteria Bacterial Genes Bacterial Infections Biochemical Campylobacter Cells Columnar Epithelium Critical Pathways Data Disease Engineering Environment Epithelial Cells Epithelium Exhibits Flow Cytometry Fractionation Gallbladder Gastrointestinal tract structure Genes Growth Histology Immune Immune response Immunohistochemistry Infection Infiltration Interferons Intestines Invaded Investigation Listeria monocytogenes Liver Metabolic Metabolic Pathway Modeling Molecular Morbidity - disease rate Mucous body substance Mus Nature Nutrient Nutrient availability 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 cell growth 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

项目摘要

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.

项目摘要单核细胞增生李斯特菌（Lm）致病机制的一个关键研究不足的部分是哺乳动物的定植胆囊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，并作为粪便分泌细菌的来源，这些细菌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增长的性质，胆囊和确定细菌代谢和应激反应途径的殖民化的关键小鼠胆囊。为此，我们提出了我们的新的离体Lm胆囊模型的初步数据，使用来自非人灵长类动物（NHP）的器官进行定殖。这些结果为调查奠定了基础转化为Lm在胆囊腔中复制所必需的特定基因和途径。这一目标本研究的目的有三：（1）将胆囊定义为Lm的复制生态位。为了做到这一点，我们将确定Lm在胆囊中的定位，并确定在胆囊中可用的代谢物。胆囊腔(2)确定胆囊定植所需的Lm基因。在这里，荧光报告菌株将被工程化以鉴定在胆囊中被激活的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，重点是胆囊定植。(3)确定免疫应答对Lm暴龙雷克斯感染的作用。我们的方法在技术上是创新的，因为它利用了我们新的NHP胆囊定植模型全面评估细菌基因在这个独特的生态位复制的重要性。这些研究的结果将重要的是，他们将揭示细菌病原体如何在胆囊中复制，并有可能发现治疗靶点以减少肠道病原体的定植和传播。