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：
10219076
负责人：
JOHN S GUNN
金额：
$ 23.1万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219076
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.

项目摘要沙门氏菌是肠杆菌科，引起人类和动物的各种疾病，包括肠发热和胃肠炎。伤寒，主要由沙门氏菌引起 Enterica血清Typhi（S。Typhi），导致威胁生命的全身性疾病每年在全球范围内每年都有明显的发病率和死亡率。大约5％的感染S的个体。 Typhi成为胆囊（GB）的慢性载体，作为持久性的位置。 S. Typhi是人类因此，病原体受限，因此无症状载体代表了进一步传播的关键储层疾病。我们已经证明胆结石（GSS）有助于GB的开发和维护小鼠模型中的托架（利用鼠伤寒链球菌，导致鼠伤寒的小鼠疾病）在人类中，用作沙门氏菌附着并形成保护性生物膜的底物。因此，生物膜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，对传统治疗方法提出了挑战。如何鼠伤寒链球菌在生物膜发育过程中颠覆了初始免疫反应，并建立了慢性感染理解很差。免疫逃生可能涉及细胞外基质（ECM）成分，但负责的因素尚不清楚。我们将该建议重点放在冰纤维/pili上，表面附属物是鼠伤伤了生物膜的形成所需受体。虽然已发表的报告表明curli并未在S. typhi中产生，但我们的初步数据证明它是生产的，但可以与伤寒链霉菌不同。此外，我们证明在人胆汁中（但不是小鼠或牛胆）中卷curli基因表达增强了约30倍。我们通过定义涉及卷质基因表达的基因，特别是那些反应的基因来解决我们的假设对于人类的胆汁，人类胆汁中介导基因激活的因素，以及从GSS上产生Curli 小鼠模型和肯尼亚的人类载体。确定卷卷期间的表达在这个研究的器官中发展持续感染，并具有专业知识结果和研究它将对该领域产生强大和持续的影响，并将确定关键重点关注未来工作的拐点。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Salmonella Biofilms Tolerate Hydrogen Peroxide by a Combination of Extracellular Polymeric Substance Barrier Function and Catalase Enzymes.

DOI：
10.3389/fcimb.2021.683081
发表时间：
2021
期刊：
Frontiers in cellular and infection microbiology
影响因子：
5.7
作者：
Hahn MM;González JF;Gunn JS
通讯作者：
Gunn JS

The Effect of the Gallbladder Environment during Chronic Infection on Salmonella Persister Cell Formation.

DOI：
10.3390/microorganisms10112276
发表时间：
2022-11-16
期刊：
Microorganisms
影响因子：
4.5
作者：
González JF;Hitt R;Laipply B;Gunn JS
通讯作者：
Gunn JS

Enhanced biofilm and extracellular matrix production by chronic carriage versus acute isolates of Salmonella Typhi.

DOI：
10.1371/journal.ppat.1009209
发表时间：
2021-01
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Devaraj A;González JF;Eichar B;Thilliez G;Kingsley RA;Baker S;Allard MW;Bakaletz LO;Gunn JS;Goodman SD
通讯作者：
Goodman SD

Salmonella Biofilm Formation, Chronic Infection, and Immunity Within the Intestine and Hepatobiliary Tract.