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：
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
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/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

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.

项目摘要李斯特菌单核细胞增生李斯特菌（LM）的发病机理的一部分是哺乳动物的定植胆囊。胆囊是包括LM在内的多种肠道病原体的主要细菌晶状体沙门氏菌和弯曲杆菌，并作为有可能有可能有可能的细菌的来源增加这些食源性病原体的传播。在这里，我们将剖析LM增长的性质胆囊并确定细菌代谢和应激反应途径对于定植至关重要鼠胆囊。为此，我们介绍了我们新颖的lm胆囊实体模型的初步数据使用非人类素数（NHP）的器官定植。这些结果为调查奠定了基础进入胆囊管腔中LM复制所需的特定基因和途径。目标的目标提案将以三个特定的目的来完成：（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，并定义可用的代谢物胆囊管腔。（2）确定胆囊定植所需的LM基因。在这里，荧光将设计记者应变以识别在胆囊中激活的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，以发病的作用，重点是胆囊殖民化。（3）确定对LM ∆REX感染的免疫增强响应的作用。我们的方法在技术上具有创新性，因为它利用了我们的NHP胆囊殖民化的新型模型在全球范围内评估细菌基因在这个独特的利基市场中对复制很重要的基因。这些研究的结果将意义重大，因为它们将发现细菌病原体如何在胆囊中复制，并有可能发现治疗靶标，以减少促进病原体的定殖和扩散。