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.

项目摘要 沙门氏菌是肠杆菌科，在人类和动物中引起一系列疾病， 包括肠（伤寒）热和胃肠炎。伤寒，主要由沙门氏菌引起 伤寒沙门氏菌（S.伤寒），导致危及生命的全身性疾病， 每年在世界范围内发生严重的发病率和死亡率。大约5%的人感染了S。 伤寒成为胆囊（GB）作为持久性部位的慢性携带者。S.伤寒是人类- 限制性病原体，因此无症状携带者是进一步传播的关键水库。 疾病我们已经证明，胆结石（GS）援助的发展和维持GB 小鼠模型中的运载（利用S.鼠伤寒（Typhimurium），在小鼠中引起类似伤寒的疾病） 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，在本发明中， 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力的耐受性，对传统的治疗方法提出了挑战。如何 S.伤寒破坏生物膜形成过程中的初始免疫反应，建立慢性感染 是很难理解的。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。我们把这个建议集中在卷曲纤维/皮利，表面附属物， 需要S。鼠伤寒生物膜形成，介导附着，并通过模式识别进行检测 受体。虽然已发表的报告表明curli不是在S。伤寒，我们的初步数据 表明它是产生的，但可能与S不同。鼠伤寒而且我们 证明了curli基因表达在人胆汁中增强了~30倍（但在小鼠或牛胆汁中没有）。我们 通过定义参与curli基因表达的基因来解决我们的假设，特别是那些响应curli基因表达的基因。 人胆汁中介导基因激活的因子，以及来自人胆汁的GSs的curli的产生， 小鼠模型和肯尼亚的人类携带者。确定curli在 在这个未充分研究的器官中发生持续性感染，并且具有专业知识，初步 成果和审查工具，将对实地产生强大和持续的影响，并将确定关键的 未来工作重点的转折点。