Alternative Approaches for E. faecalis Infections

粪肠球菌感染的替代方法

基本信息

项目摘要

DESCRIPTION (provided by applicant): Enterococci are the 3rd most common cause of community-onset infective endocarditis (IE) and the 2nd to 3rd most common cause of healthcare-associated infections overall (but are 1st-2nd in healthcare-associated IE, with E. faecalis (Efs) predominating). Antimicrobial resistance likely facilitates establishment of enterococci in the hospital setting and in the flora of hospitalized patients, and certainly makes therapy more difficult, particularly for IE. Our recent work has focused on the contributions to pathogenesis of Efs adherence to ECM proteins, a phenotype not usually seen after standard in vitro growth. We identified Ace and showed that it is an Adhesin to Collagen (CN) of Efs, that factors like serum, CN and growth at 46 C induce ace expression, that the ubiquitous ace gene is important in Efs experimental IE, that immunization with Ace protects against EIE, and we delineated the molecular mechanism of Ace's binding to CN. Our work on other Efs surface proteins which, like Ace, have deviant Ig-like folds, led us to the "Ebp" genes and their role in Endocarditis, Biofilm and Pilus formation; later we showed that the ebp genes are part of the Efs core genome and are also important in ascending murine UTIs and for a second CN-adherence phenotype. We also identified a family of fibrinogen (FG)-binding MSCRAMMs that require the presence of Ebp pili to confer FG adherence to Efs cells and, recently, we showed that serum a) elicits, during growth, ECM adherence, and also b) serves as an activator of adherence, perhaps by forming bridges between ECM proteins and adhesins. In this renewal, plans for Ace are to 1) demonstrate (by introducing, into ace, the mutations that decrease in vitro CN-binding of rec-Ace) that the attenuation seen with ace knock-out mutants is specifically associated with loss of Ace's CN- binding activity (vs. an unrelated effect due to loss of this surface protein), 2) explore the efficacy of anti-Ace mAbs in preventing Efs IE and the molecular basis by which displacing mAbs function, and 3) determine the mechanism of ace induction by serum and CN. Goals relating to Ebp pili and FG adhesins are to 1) localize Ebp pilin subunits within pili and define the role of these subunits and two sortases in pilus biogenesis, 2) identify the mechanism responsible for pilus-associated (non-Ace) CN adherence and the role of individual pilins in biofilm, cell adherence, and virulence, 3) determine the basis for elimination of FG adherence in pilus mutants even though FG-adhesins are still present, 4) determine if immunity against Ebp subunits prevents experimental IE, and 5) investigate the mechanism by which serum elicits pilus formation and conditions and mechanisms for pilus regulation. Finally, we will investigate a possible additive effect between ace and ebpABC in EIE and between mAbs to them in inhibition of CN adherence of Efs cells. Our long-range goals are 1) to understand the mechanism of action of these adhesins in pathogenesis, with 2) the hope that the results of our studies will form the basis for rational design of modalities to prevent or ameliorate Efs infections, and 3) will provide a better understanding of how this organism interacts with the human host.
描述(由申请人提供):肠球菌是社区发病的感染性心内膜炎 (IE) 的第三大常见原因,也是医疗保健相关感染的第二至第三大常见原因(但在医疗保健相关的 IE 中排名第一至第二,其中粪肠球菌 (Efs) 占主导地位)。抗菌药物耐药性可能会促进肠球菌在医院环境和住院患者菌群中的建立,并且肯定会使治疗变得更加困难,特别是对于 IE。我们最近的工作重点是 Efs 粘附 ECM 蛋白对发病机制的贡献,这是标准体外生长后通常不会出现的表型。我们鉴定了 Ace,并表明它是 Efs 的胶原粘附素 (CN),血清、CN 和 46°C 生长等因素诱导 ace 表达,普遍存在的 ace 基因在 Efs 实验 IE 中很重要,Ace 免疫可以预防 EIE,并且我们描述了 Ace 与 CN 结合的分子机制。我们对其他 Efs 表面蛋白(如 Ace)的研究,具有异常的 Ig 样折叠,使我们发现了“Ebp”基因及其在心内膜炎、生物膜和菌毛形成中的作用;后来我们证明 ebp 基因是 Efs 核心基因组的一部分,并且对于上行性小鼠尿路感染和第二种 CN 粘附表型也很重要。我们还鉴定了一个纤维蛋白原 (FG) 结合 MSCRAMM 家族,它们需要 Ebp 菌毛的存在才能赋予 FG 粘附到 Efs 细胞上,最近,我们表明血清 a) 在生长过程中引发 ECM 粘附,b) 可能通过在 ECM 蛋白和粘附素之间形成桥梁来充当粘附激活剂。在本次更新中,Ace 的计划是 1) 证明(通过在 ace 中引入减少 re-Ace 体外 CN 结合的突变),ace 敲除突变体所观察到的减弱与 Ace 的 CN 结合活性的丧失特别相关(相对于由于该表面蛋白的丧失而产生的不相关效应),2) 探索抗 Ace mAb 在预防 Efs IE 和 取代 mAb 功能的分子基础,3) 确定血清和 CN 诱导 ACE 的机制。与 Ebp 菌毛和 FG 粘附素相关的目标是 1) 将 Ebp 菌毛蛋白亚基定位在菌毛内,并定义这些亚基和两种分选酶在菌毛生物发生中的作用,2) 确定负责菌毛相关(非 Ace)CN 粘附的机制以及单个菌毛蛋白在生物膜、细胞粘附和毒力中的作用,3) 确定消除菌毛突变体中 FG 粘附的基础,甚至 尽管 FG-粘附素仍然存在,4) 确定针对 Ebp 亚基的免疫是否可以预防实验性 IE,5) 研究血清引发菌毛形成的机制以及菌毛调节的条件和机制。最后,我们将研究 EIE 中 ace 和 ebpABC 之间以及它们之间的 mAb 之间可能存在的累加效应,以抑制 Efs 细胞的 CN 粘附。我们的长期目标是 1) 了解这些粘附素在发病机制中的作用机制,2) 希望我们的研究结果能够为合理设计预防或改善 Efs 感染的方式奠定基础,3) 更好地了解这种生物体如何与人类宿主相互作用。

项目成果

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BARBARA E MURRAY其他文献

BARBARA E MURRAY的其他文献

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{{ truncateString('BARBARA E MURRAY', 18)}}的其他基金

Developing a better understanding of expression and function of PBP5-R of Enterococcus faecium for future development of therapeutic modalities for VRE infections
更好地了解屎肠球菌 PBP5-R 的表达和功能,以便未来开发 VRE 感染的治疗方式
  • 批准号:
    9534883
  • 财政年份:
    2018
  • 资助金额:
    $ 68.66万
  • 项目类别:
Does ampicillin resistance or clade type determine GI colonization by E. faecium?
氨苄西林耐药性或进化枝类型是否决定了屎肠球菌在胃肠道的定植?
  • 批准号:
    8427005
  • 财政年份:
    2013
  • 资助金额:
    $ 68.66万
  • 项目类别:
Does ampicillin resistance or clade type determine GI colonization by E. faecium?
氨苄西林耐药性或进化枝类型是否决定了屎肠球菌在胃肠道的定植?
  • 批准号:
    8605515
  • 财政年份:
    2013
  • 资助金额:
    $ 68.66万
  • 项目类别:
Importance of adhesin-like proteins of Enteroccocus faecium
屎肠球菌粘附素样蛋白的重要性
  • 批准号:
    7544950
  • 财政年份:
    2006
  • 资助金额:
    $ 68.66万
  • 项目类别:
Importance of adhesin-like proteins of Enteroccocus faecium
屎肠球菌粘附素样蛋白的重要性
  • 批准号:
    7752774
  • 财政年份:
    2006
  • 资助金额:
    $ 68.66万
  • 项目类别:
Importance of adhesin-like proteins of Enteroccocus faecium
屎肠球菌粘附素样蛋白的重要性
  • 批准号:
    7335571
  • 财政年份:
    2006
  • 资助金额:
    $ 68.66万
  • 项目类别:
Importance of adhesin-like proteins of Enteroccocus faecium
屎肠球菌粘附素样蛋白的重要性
  • 批准号:
    7156214
  • 财政年份:
    2006
  • 资助金额:
    $ 68.66万
  • 项目类别:
Importance of adhesin-like proteins of Enteroccocus faecium
屎肠球菌粘附素样蛋白的重要性
  • 批准号:
    7022475
  • 财政年份:
    2006
  • 资助金额:
    $ 68.66万
  • 项目类别:
ALTERNATIVE APPROACHES FOR E FAECALIS INFECTIONS
粪肠球菌感染的替代方法
  • 批准号:
    6532827
  • 财政年份:
    2000
  • 资助金额:
    $ 68.66万
  • 项目类别:
ALTERNATIVE APPROACHES FOR E FAECALIS INFECTIONS
粪肠球菌感染的替代方法
  • 批准号:
    6822688
  • 财政年份:
    2000
  • 资助金额:
    $ 68.66万
  • 项目类别:

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