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

• 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
• 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' 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

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.

项目总结 沙门氏菌是一种肠杆菌科细菌，能引起人类和动物的一系列疾病， 包括肠道(伤寒)热和胃肠炎。伤寒，主要由沙门氏菌引起 伤寒沙门氏菌引起一种危及生命的全身性疾病 全世界每年的发病率和死亡率都很高。大约5%的感染S。 伤寒成为慢性携带者，以胆囊(GB)为持久性部位。伤寒沙门氏菌是人类- 有限的病原体，因此无症状携带者是进一步传播的关键宿主 疾病。我们已经证明，胆结石(GSS)有助于GB的发展和维护 小鼠模型中的携带(利用引起小鼠伤寒类疾病的鼠伤寒沙门氏菌) 在人类中，作为沙门氏菌附着并形成保护性生物膜的底物。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是 对抗生素和宿主免疫的顽固性，对传统的治疗方法提出了挑战。多么 伤寒沙门氏菌在生物膜发育过程中颠覆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。我们将重点放在卷曲纤维/毛发、表面附属物上 鼠伤寒沙门氏菌生物膜形成所必需的，中介附着，并通过模式识别来感知 感受器。虽然已发表的报告表明沙门氏菌不会产生卷曲，但我们的初步数据 表明它是产生的，但可能受到不同于鼠伤寒沙门氏菌的监管。此外，我们 证明Curli基因在人胆汁(而不是小鼠或牛胆汁)中的表达增加了约30倍。我们 通过定义与Curli基因表达有关的基因，特别是那些响应的基因，来解决我们的假设 对于人胆汁，人胆汁中的因素介导了基因的激活，并对GSS产生了凝集作用。 小鼠模型和来自肯尼亚的人类携带者。测定过程中Curli的表达 在这个研究不足的器官中持续感染的发展，并具有专业知识，初步 审查结果和工具，将对该领域产生强大和持续的影响，并将确定关键 今后工作要重点关注的拐点。