Mechanisms of Enterococcal Niche Modulation during Polymicrobial Infection

项目总结/摘要 在美国，肠球菌是医院获得性感染的主要原因， 导尿膀胱和伤口的机会致病菌。肠球菌在70%的 伤口感染，通常与生物膜内生长的多个属相关。存在知识差距， 我们对粪肠球菌如何促进多种微生物感染的发病机制的理解。 本研究的长期目标是识别、定义和利用E。粪 调节其环境以改变体内多种微生物感染的发病机制。具体目标是 探索性R21研究基金是为了确定介导E. faecalis和E.大肠杆菌相互作用 伤口感染模型研究假设E.粪便改变了当地的环境 在多微生物感染期间，通过输出提示E.大肠杆菌毒力。这个假设是基于 初步数据表明，E. faecalis增强了E.多菌内大肠杆菌 在体外铁限制条件下和在体内伤口感染期间的生物膜。为了解决这个假设 并实现本建议的目标，屏幕为E。faecalis效应分子和E.杆菌 反应途径的研究将在以下几个方面进行：1）鉴定E.粪便因子， 增加E. coli生物膜生长; 2）鉴定E.大肠杆菌基因所需的扩增生长， E.粪便线索。在完成这些目标后，该项目的预期成果将包括： 鉴定了所有参与E. faecalis + E.大肠杆菌在感染过程中协同作用。 这项研究的发现是重要的，因为它们将是第一个识别E。粪便因子， 促进慢性、多种微生物、生物膜相关感染。该方法利用了一种创新的 模拟体内感染环境方面的体外平台， 由E.在铁限制宿主体内的粪菌。总之，这项工作具有很大的 承诺1）了解感染期间发生的多微生物协同作用的分子基础，以及2） 确定新的抗感染和治疗靶点，以治疗日益常见的耐药性 多种微生物感染

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.