Mechanisms of Enterococcal Niche Modulation during Polymicrobial Infection

多种微生物感染期间肠球菌生态位调节的机制

• 批准号: 9301465
• 负责人: Kimberly Ann Kline
• 金额: $ 16.82万
• 依托单位: NANYANG TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-21 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301465
• 关键词: Address; Affect; Age; Anti-Infective Agents; Antibiotic Resistance; Assimilations; Bladder; Catheters; Chronic; Comorbidity; Cues; Data; Development; Diffuse; Drug resistance; Elderly; Enterococcus; Enterococcus faecalis; Environment; Escherichia coli; Genes; Genetic; Genetic Transcription; Goals; Growth; Hospitals; In Vitro; Incidence; Individual; Infection; Intervention; Investigation; Iron; Knowledge; Lead; Maps; Mediating; Microbial Biofilms; Mission; Modeling; Molecular; Multi-Drug Resistance; Mus; Nosocomial Infections; Obesity; Organism; Outcome; Pathogenesis; Pathway interactions; Population; Prevalence; Production; Public Health; Research; Research Project Grants; Resistance; Siderophores; Signal Pathway; System; United States National Institutes of Health; Urinary tract; Virulence; Work; Wound Infection; base; candidate identification; catheter associated UTI; design; diabetic; experimental study; follow-up; gene product; immune clearance; in vivo; innovation; microbial; novel; pathogen; prevent; programs; resistant strain; response; synergism; therapeutic target

PROJECT SUMMARY/ABSTRACT Enterococci are a leading cause of hospital-acquired infections in the USA, where they are frequent opportunistic pathogens of the catheterized urinary bladder and wounds. Enterococci are found in up to 70% of wound infections, often in association with multiple genera growing within biofilms. There is a knowledge gap in our understanding of how Enterococcus faecalis contributes to the pathogenesis of polymicrobial infections. The long term goal of this research is to identify, define, and harness mechanisms by which E. faecalis modulates its environment to alter the pathogenesis of polymicrobial infections in vivo. The specific goal of this exploratory R21 research grant is to identify factors that mediate E. faecalis and E. coli interactions in a murine wound infection model. The hypothesis under investigation is that E. faecalis changes the local environmental during polymicrobial infection by exporting molecules that cue E. coli virulence. This hypothesis is based on preliminary data showing that E. faecalis enhances the growth and virulence of E. coli within polymicrobial biofilms in vitro under iron-limited conditions and in vivo during wound infection. To address this hypothesis and achieve the goals of this proposal, screens for both the E. faecalis effector molecules and the E. coli responsive pathways will be performed in the following specific aims: 1) Identify the E. faecalis factors that augment E. coli biofilm growth, and 2) Identify the E. coli genes required for augmented growth in response to E. faecalis cues. Upon completion of these aims, the expected outcomes of this project will include the identification of all of the non-essential genes that are involved in E. faecalis + E. coli synergy during infections. The findings in this study are important because they will be the first to identify E. faecalis factors that promotes chronic, polymicrobial, biofilm-associated infections. The approach takes advantage of an innovative in vitro platform that mimics aspects of the in vivo infection environment to specifically examine pathways of microbial synergy conferred by E. faecalis within the iron-restricted host. Altogether, this work holds great promise for 1) understanding the molecular basis of polymicrobial synergies that occur during infection, and 2) identifying new anti-infective and therapeutic targets to treat increasingly common and often drug-resistance polymicrobial infections.

项目摘要/摘要 在美国，肠球菌是医院获得性感染的主要原因，在那里它们经常发生。 导尿管膀胱和伤口的机会性病原体。肠球菌存在于高达70%的 伤口感染，通常与生物膜内生长的多个属有关。在……方面存在知识差距 我们对粪肠球菌如何在多菌感染的发病机制中做出贡献的理解。 这项研究的长期目标是识别、定义和控制粪肠球菌感染机制。 调节其环境以改变体内多菌感染的发病机制。这一行动的具体目标是 探索性R21研究基金是为了确定在小鼠体内介导粪肠球菌和大肠杆菌相互作用的因素。 创面感染模型。正在调查的假说是粪肠球菌改变了当地的环境 在多菌感染期间，通过输出提示大肠杆菌毒力的分子。这一假设是基于 初步数据显示，粪肠球菌在多菌剂中促进了大肠杆菌的生长和毒力 铁限制条件下的体外生物膜和伤口感染时的体内生物膜。要解决这一假设 并实现这项提案的目标，对粪肠球菌效应器分子和大肠杆菌进行筛选 响应途径将在以下特定目标中进行：1)确定粪肠球菌因子， 促进大肠杆菌生物膜生长，以及2)鉴定促进生长所需的大肠杆菌基因，以响应 粪便石斑菌。在完成这些目标后，本项目的预期成果将包括 确定在感染过程中与粪肠球菌+大肠杆菌协同作用有关的所有非必需基因。 这项研究的发现很重要，因为他们将第一次确定粪肠球菌的因子 促进慢性、多菌、生物被膜相关感染。该方法利用了一种创新的 体外平台，模拟体内感染环境的各个方面，专门检查感染途径 粪肠球菌在铁限制宿主内的微生物协同作用。总而言之，这部作品很有说服力 承诺1)理解在感染过程中发生的多菌协同作用的分子基础，以及2) 确定新的抗感染和治疗靶点以治疗日益常见的、往往是耐药的 多菌感染。

项目成果

Enterococcal Metabolite Cues Facilitate Interspecies Niche Modulation and Polymicrobial Infection.

• DOI: 10.1016/j.chom.2016.09.004
• 发表时间: 2016-10-12
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Keogh D;Tay WH;Ho YY;Dale JL;Chen S;Umashankar S;Williams RBH;Chen SL;Dunny GM;Kline KA
• 通讯作者: Kline KA

Escherichia coli BarA-UvrY regulates the pks island and kills Staphylococci via the genotoxin colibactin during interspecies competition.

• DOI: 10.1371/journal.ppat.1010766
• 发表时间: 2022-09
• 期刊: PLoS pathogens
• 影响因子: 6.7