The Impact of Vancomycin-Resistant Entercoccus on Clostridium difficile Infection

项目总结 艰难梭菌是美国最常见的医院病原体，也是一种紧急的 世界范围内的公共卫生威胁。在过去的十年中，艰难梭菌的发病率、严重性和成本 感染(CDI)急剧增加；然而，控制这一广泛疾病范围的因素 目前仍不清楚。CDI的主要风险因素是抗生素的使用，这降低了对C. 通过改变驻留的肠道微生物群来产生艰难的细菌。有趣的是，医院内的主要病原体万古霉素- 耐药肠球菌(VRE)与艰难梭菌有许多共同的危险因素，这些病原体通常是 一起在胃肠道中被发现。此外，VRE的定植与更严重的C. 在艰难梭菌相关疾病和部分患者中，CDI增加了VRE引起的菌血症风险。 尽管有这些强烈的联系，但几乎没有工作来探索分子之间的相互作用 肠球菌和艰难梭菌在感染过程中，目前尚不清楚这些病原体的共存有什么影响 艰难梭菌相关疾病。物种间的相互作用可以归因于许多 包括CDI在内的多种微生物感染和细菌之间的串扰与疾病的恶化有关 几种疾病。肠球菌与CDI和肠道微生物区系易感性增加有关 CDI患者的肠球菌高度丰富。在过量补锌后，共生 肠球菌在微生物区系中高度丰富，这导致对CDI的易感性增加，加重 艰难梭菌相关疾病，以及高水平的肠球菌易位到肝脏。初步数据 表明在培养中，肠球菌和艰难梭菌直接相互作用，这种相互作用改变了毒力和 这两种病原体的行为。在这一应用中，我们建议阐明 肠球菌和艰难梭菌，并定义这些相互作用对易感性和严重程度的影响 CDI公司。我们假设：(I)肠球菌通过改变肠道环境而增加对CDI的易感性 加强艰难梭菌的定植和(Ii)肠球菌和艰难梭菌在胃肠道的共存 肠道促进了这两种重要病原体之间的相互作用，从而增加了持久性并加剧了 CDI期间的疾病。我们计划通过一系列综合的具体目标来检验这三个假说。第一, 我们将剖析肠球菌丰度与艰难梭菌和 确定肠球菌对艰难梭菌在小鼠体内毒力的贡献(目标1)。然后我们将定义如何 这些病原体在感染期间相互作用，并检查细菌串扰对疾病的影响(目标2)。 这些实验将阐明VRE对CDI和Will的易感性、严重性和复发的影响 大大增加我们对艰难梭菌如何与其他常见病原微生物群相互作用的了解 在感染期间。完成这项提议所获得的见解将为小说奠定基础 旨在破坏促进艰难梭菌感染的分子相互作用的治疗学。

PROJECT SUMMARY Clostridium difficile is the most commonly reported nosocomial pathogen in the United States and an urgent public health threat worldwide. Over the past decade, incidence, severity, and costs associated with C. difficile infection (CDI) have increased dramatically; however, the factors that govern this broad spectrum of disease remain unclear. The primary risk factor for CDI is antibiotic use, which reduces colonization resistance to C. difficile by altering the resident gut microbiota. Interestingly, the major nosocomial pathogen vancomycin- resistant Enterococcus (VRE) shares numerous risk factors with C. difficile and these pathogens are commonly found together in the gastrointestinal tract. Moreover, colonization with VRE is associated with more severe C. difficile-associated disease and in subsets of patients, CDI increases the risk of bacteremia due to VRE. Despite these strong associations, little work has been done to explore the molecular interactions between Enteroccoci and C. difficile during infection and it is unclear what impact co-occurrence of these pathogens has on C. difficile-associated disease. Interspecies interactions can be attributed to the development of numerous polymicrobial infections, including CDI, and cross talk between bacteria is associated with exacerbation of several diseases. Enterococcus is associated with increased susceptibility to CDI and the gut microbiota of patients with CDI is highly enriched with Enterococci. Following excess Zn supplementation, commensal Enterococci are highly enriched in the microbiota, which leads to increased susceptibility to CDI, exacerbation of C. difficile-associated disease, and high levels of Enterococcus translocation to the liver. Preliminary data suggests that in culture, Enterococcus and C. difficile directly interact and this cross-talk alters virulence and behavior of these two pathogens. In this application, we propose to elucidate the interactions between Enterococcus and C. difficile and define the impact that these interactions have on susceptibility and severity of CDI. We hypothesize that (i) Enterococcus increases susceptibility to CDI by altering the landscape of the gut to enhance C. difficile colonization and (ii) co-occurrence of Enterococcus and C. difficile in the gastrointestinal tract facilitates cross-talk between these two important pathogens that increases persistence and exacerbates disease during CDI. We plan to test these three hypotheses through a series of integrated Specific Aims. First, we will dissect the relationship between Enterococcus abundance and susceptibility to C. difficile and determine the contribution of Enterococcus to C. difficile virulence in mice (Aim 1). We will then define how these pathogens interact during infection and examine the impact of bacterial cross-talk on disease (Aim 2). These experiments will elucidate the impact of VRE on susceptibility, severity, and recurrence of CDI and will substantially increase our understanding of how C. difficile interacts with other common pathogenic microbiota during infection. The insights gained by completion of this proposal will lay the foundation for novel therapeutics that aim to disrupt the molecular interactions that facilitate C. difficile infection.