Regulation and role of Salmonella curli during chronic infection

卷曲沙门氏菌在慢性感染过程中的调节和作用

基本信息

批准号：
10040665
负责人：
JOHN S GUNN
金额：
$ 19.25万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-17 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10040665
关键词：
Address Alzheimer&apos s Disease Amyloid Amyloid Proteins Animals Antibiotics Bacteria Bile fluid Carrier State Cellulose Cessation of life Cholelithiasis Chronic Clinical Communicable Diseases Complex DNA Data Defect Development Disease Enteral Enterobacteriaceae Environment Escherichia coli Extracellular Matrix Fiber Future Gallbladder Gastroenteritis Gene Activation Gene Expression Gene Expression Regulation Genes Goals Human Immune Immune response Immune system Immunity In Vitro Individual Infection Inflammation Kenya Knowledge Life Link Maintenance Mediating Methods Microbial Biofilms Modeling Molecular Morbidity - disease rate Mus Organ Outcome Pattern recognition receptor Phenotype Pilum Polysaccharides Production Proteins Publishing Regulation Reporting Research Role Salmonella Salmonella enterica Salmonella infections Salmonella typhi Salmonella typhimurium Sepsis Site Structure Surface Systemic disease Temperature Therapeutic Typhoid Fever Urinary tract infection Work acute infection antimicrobial appendage chemokine chronic infection comparative cytokine gastrointestinal immune clearance innovation interest mortality mouse model pathogen tool transcription factor transmission process

项目摘要

PROJECT SUMMARY Salmonellae are Enterobacteriaceae that cause a spectrum of diseases in humans and animals, including enteric (typhoid) fever and gastroenteritis. Typhoid fever, caused primarily by Salmonella enterica serovar Typhi (S. Typhi), results in a life-threatening systemic disease that is responsible for significant morbidity and mortality annually worldwide. Approximately 5% of individuals infected with S. Typhi become chronic carriers with the gallbladder (GB) as the site of persistence. S. Typhi is a human- restricted pathogen, therefore asymptomatic carriers represent a critical reservoir for further spread of disease. We have demonstrated that gallstones (GSs) aid in the development and maintenance of GB carriage in a mouse model (utilizing S. Typhimurium, which causes a typhoid-fever like disease in mice) and in humans, serving as a substrate to which salmonellae attach and form a protective biofilm. Thus, biofilm formation is a key step in the establishment of carriers. Salmonella in biofilms are known to be recalcitrant to antibiotics and host immunity, presenting a challenge for traditional treatment methods. How S. Typhi subverts the initial immune response during biofilm development and establishes chronic infection is poorly understood. Immune escape likely involves extracellular matrix (ECM) components, but the responsible factors are not known. We focus this proposal on curli fibers/pili, surface appendages that are required for S. Typhimurium biofilm formation, mediate attachment and are sensed by pattern recognition receptors. While published reports suggest curli is not produced in S. Typhi, our preliminary data demonstrates that it is produced, but may be regulated differently than in S. Typhimurium. Furthermore, we demonstrate that curli gene expression is enhance ~30-fold in human bile (but not mouse or ox bile). We address our hypotheses by defining genes involved in curli gene expression, specifically those responding to human bile, the factors in human bile mediating gene activation, and the production of curli on GSs from the mouse model and from human carriers in Kenya. Determining the expression of curli during development of persistent infection in this understudied organ, and having the expertise, preliminary results and tools to examine it, will have a strong and sustained influence on the field and will identify key inflection points on which to focus future work.

项目概要沙门氏菌是肠杆菌科细菌，可引起人类和动物的一系列疾病，包括肠热（伤寒）热和胃肠炎。伤寒，主要由沙门氏菌引起伤寒肠杆菌（S. Typhi）会导致危及生命的全身性疾病，导致全世界每年都有显着的发病率和死亡率。大约 5% 的人感染了链球菌。伤寒成为慢性携带者，并以胆囊（GB）作为持续存在的部位。伤寒沙门氏菌是一种人类—— 限制性病原体，因此无症状携带者是进一步传播的关键储存库疾病。我们已经证明胆结石 (GS) 有助于 GB 的发育和维持小鼠模型中的携带（利用鼠伤寒沙门氏菌，它会导致小鼠出现类似伤寒的疾病）在人类中，作为沙门氏菌附着并形成保护性生物膜的基质。因此，生物膜的形成是载体建立的关键步骤。已知生物膜中的沙门氏菌对抗生素和宿主免疫具有抵抗力，对传统治疗方法提出了挑战。如何伤寒沙门氏菌破坏生物膜形成过程中的初始免疫反应并建立慢性感染人们对此知之甚少。免疫逃逸可能涉及细胞外基质 (ECM) 成分，但责任因素尚不清楚。我们将此提案的重点放在卷曲纤维/菌毛、表面附属物上鼠伤寒沙门氏菌生物膜形成所必需的，介导附着并通过模式识别来感知受体。虽然已发表的报告表明卷曲蛋白不是在伤寒沙门氏菌中产生的，但我们的初步数据表明它是产生的，但其调节方式可能与鼠伤寒沙门氏菌不同。此外，我们证明 curli 基因表达在人胆汁中增强了约 30 倍（但不是小鼠或牛胆汁）。我们通过定义参与 curli 基因表达的基因，特别是那些响应的基因来解决我们的假设人胆汁中介导基因激活的因素，以及 GS 上 Curli 的产生小鼠模型和来自肯尼亚的人类携带者。确定curli期间的表达在这个被研究的器官中发生持续性感染，并具有专业知识，初步结果和检验它的工具将对该领域产生强大而持续的影响，并将确定关键未来工作重点关注的拐点。