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Salmonella chronic infection: Biofilm matrix factors and innate immune tolerance

沙门氏菌慢性感染：生物膜基质因子和先天免疫耐受

基本信息

批准号：
10319614
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：
2020-12-17 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319614
关键词：
Address Affect Animals Antibiotics Architecture Bacteria Bacterial Infections Biological Assay Carrier State Chemotaxis Cholelithiasis Chronic Clinical Complement DNA Data Dependence Development Disease Enteral Enterobacteriaceae Environment Gallbladder Gastroenteritis Goals Human Immune Immune Evasion Immune Tolerance Immune response Immune system Immunity Immunology procedure In Vitro Individual Infection Kenya Knowledge Life Link Maintenance Methods Microbial Biofilms Microscopy Modeling Molecular Morbidity - disease rate Mus Natural Immunity Organ Outcome Pathogenicity Phagocytes Polymers Polysaccharides Prevention Production Proteins Regulation Research Respiratory Burst Role Salmonella Salmonella typhi Salmonella typhimurium Site Structure Surface Systemic disease Techniques Therapeutic Typhoid Fever Work acute infection antimicrobial antimicrobial peptide chronic infection confocal imaging extracellular immune clearance immune function immunoregulation improved in vivo innate immune function innovation interest mortality mouse model mutant neutrophil novel therapeutics pathogen prevent residence response therapy development

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 annually responsible for significant morbidity and mortality worldwide. Approximately 5% of individuals infected with S. Typhi become chronic carriers with the gallbladder (GB) as the primary 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. A hallmark of chronic S. Typhi infections is the production of extracellular polymeric substances (EPSs) which are integral to biofilm development on GSs. How the bacteria subvert innate immunity during early stages of biofilm development and establish chronic infections is not known. Immune escape likely involves EPS, but a complete understanding of the EPSs responsible for this function is not known. We hypothesize one or more EPS has a critical role in biofilm development and contributes to the chronic pathogenicity of S. Typhi biofilms via innate immune evasion. Identification of the essential EPS(s) will allow us to determine the mechanism of immune evasion, likely due to a combination of a physical barrier function and regulation of innate host responses. To build on our prelinminary data, we will further investigate which EPSs are responsible for this perturbation and conduct quantitative assays to evaluate innate phagocyte activity in response to WT and EPS mutant biofilms. Assays for soluable factors (e.g. antimicrobial peptides, complement) and polymorphonuclear cell (neutrophil) functions (chemotaxis, neutrophil extracellular trapping, and induction of respiratory burst) have been or will be conducted. Confocal imaging of EPSs from in vitro and in vivo GSs will determine the structural contribution of each EPS during chronic infection and will be correlated to functional assays of immune modulation. Overall, an improved understanding of how biofilms develop in vivo and how EPSs skew innate immunity will be critical for development of new treatment and prevention methods. Disruption of carrier state infections will have a significant impact on endemic S. Typhi persistence and the spread of typhoid fever.

项目摘要沙门氏菌是肠杆菌科，其在人类和动物中引起一系列疾病，包括肠（伤寒）发烧和肠胃炎。伤寒，主要由伤寒沙门氏菌引起。伤寒），导致一种危及生命的全身性疾病，每年造成重大的发病率，全世界的死亡率。大约5%的人感染了S。伤寒成为慢性带菌者，胆囊（GB）作为主要的持久性部位。S.伤寒是一种人类限制性病原体，因此，无症状带菌者是疾病进一步传播的关键宿主。我们已经证明胆结石（GS）有助于小鼠模型中GB携带的发展和维持（利用S. 鼠伤寒杆菌，在小鼠和人类中引起伤寒样疾病，作为底物，鲑鱼附着并形成保护性生物膜。因此，生物膜的形成是建立生物膜的关键步骤。载波已知生物膜中的沙门氏菌对抗生素和宿主免疫力具有抵抗性，传统的治疗方法。慢性S.伤寒感染是细胞外聚合物的产生物质（EPS），这是不可或缺的生物膜发展的GS。细菌如何破坏先天免疫在生物膜发展的早期阶段和建立慢性感染是未知的。可能是免疫逃逸涉及EPS，但对负责此功能的EPS的完整理解尚不清楚。我们假设一种或多种EPS在生物膜形成中具有关键作用，并有助于S.伤寒生物膜通过先天免疫逃避。识别基本EPS将使我们能够确定其机制免疫逃避，可能是由于物理屏障功能和先天宿主反应的调节的组合。为了建立我们的初步数据，我们将进一步调查哪些EPS是造成这种扰动的原因，进行定量测定以评价响应于WT和EPS突变生物膜的先天吞噬细胞活性。可溶性因子（例如抗菌肽、补体）和多形细胞（中性粒细胞）的测定功能（趋化性、嗜中性粒细胞胞外捕获和呼吸爆发诱导）已经或将进行。来自体外和体内GS的EPS的共聚焦成像将确定每个EPS的结构贡献。慢性感染期间的EPS将与免疫调节的功能测定相关。总的来说，改善了解生物膜如何在体内形成，以及EPS如何扭曲先天免疫，将是发展的关键新的治疗和预防方法。携带者状态感染的中断将对特有的S.伤寒持续存在和伤寒的传播。