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 肠球菌是美国经常出现医院获得感染的主要原因 导管膀胱和伤口的机会性病原体。肠球菌最多可达70％ 伤口感染，通常与生物膜内的多个属相结合。有一个知识差距 我们对粪肠球菌如何有助于多因素感染的发病机理的理解。 这项研究的长期目标是识别，定义和利用E.粪便的机制 调节其环境以改变体内多数菌感染的发病机理。这个的具体目标 探索性R21研究赠款是为了确定介导鼠类中粪肠球菌和大肠杆菌相互作用的因素 伤口感染模型。所研究的假设是粪肠球菌改变了当地的环境 通过导出提示大肠杆菌毒力的分子，通过出口多数菌感染。该假设基于 初步数据表明，大肠杆菌增强了大肠杆菌的生长和毒力 在铁限制的条件下和伤口感染期间的体内生物膜。解决这一假设 并实现该提案的目标，用于粪肠球菌效应分子和大肠杆菌的筛选 响应途径将在以下特定目的中执行：1）确定粪肠球菌因素 增强大肠杆菌生物膜的生长，以及2）确定增强生长所需的大肠杆菌基因 E.粪便提示。完成这些目标后，该项目的预期结果将包括 在感染过程中鉴定所有与粪肠球菌 +大肠杆菌协同作用相关的非必需基因。 这项研究的发现很重要，因为它们将是第一个识别粪肠球菌因素的人 促进慢性，多因素，生物膜相关感染。该方法利用了创新的优势 体外平台模仿体内感染环境的各个方面，以专门检查 粪肠球菌在铁限制的宿主中赋予微生物协同作用。总之，这项工作很棒 有望1）了解感染过程中发生多数菌种协同作用的分子基础，以及2） 识别新的抗感染和治疗靶标，以治疗日益普遍的抗药性和耐药性 多因素感染。

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