ALTERNATIVE APPROACHES FOR E FAECALIS INFECTIONS

简介(摘自申请者摘要)：肠球菌居第3位 心内膜炎的最常见原因，仅次于链球菌和葡萄球菌，以及 医院获得性感染的第二或第三大常见原因， 分离的优势菌为粪肠球菌。抗菌剂 耐药性可能促进医院内肠球菌的建立 感染，肯定会使成功治疗变得更加困难 患者，特别是那些患有心内膜炎的患者。这一点的中心假设是 项目是通过更好地了解肠球菌，新的治疗方法或 可以开发出预防性的模式。在以前资助的赠款期间工作 鉴定和鉴定了一些抗原编码基因；a 似乎影响小鼠毒力的多糖基因簇(EPA)； 不同的黏附表型，以及一个基因ace，它似乎参与了 以及一个与辅助基因调节因子(Agr)同源的基因座。 与粪肠球菌表达有关的葡萄球菌基因座 明胶酶和一种丝氨酸蛋白酶，也影响小鼠的毒力。在这 申请，调查人员建议(1)核实粪肠球菌 AGR样位点调节GLE和SprE，并确定它们是否对 毒力；调查这些基因在粪肠球菌中的分布； 并确定肠球菌agr样位点是如何调节的，如果它， 就像葡萄球菌的agr一样，它调节着其他基因。他们还计划(2)测试 Ace(一种新发现的肠球菌胶原粘附素)的假说 是我们已经报道的坚持的原因，并且对毒力很重要； 探索Ace生产的规律；确定Ace的分布 如果Ace在人类中引起抗体反应，Ace变异的影响 (使用重组Ace和患者血清)感染粪肠球菌和IF 在感染过程中产生的抗体或重组Ace的抗体具有保护性。 在他们的第三个特定目标中，他们计划(3)确定多糖是否 基因簇是最近描述的一种粘液表型的原因 它的监管，并进一步测试它对遵守外国 物质、毒性和保护。他们还将探索一种 基于它们的反选择构建非极性缺失突变体 之前对粪肠球菌PYR基因的研究，并探索其他检测方法 这将有助于避免致命的模式。调查人员希望调查结果 这项工作将为寻找预防方法提供可靠的线索， 控制或抗击粪肠球菌感染。

DESCRIPTION (Adapted from the Applicant's Abstract): Enterococci are the 3rd most common cause of endocarditis, behind streptococci and staphylococci, and the 2nd or 3rd most common cause of hospital acquired infections, with Enterococcus faecalis being the predominant species isolated. Antimicrobial resistance likely facilitates the establishment of enterococci in nosocomial infections and certainly makes it more difficult to successfully treat patients, particularly those with endocarditis. The central hypothesis of this project is that by better understanding enterococci, new therapeutic or preventative modalities can be developed. Work during a previously funded grant identified and characterized a number of antigen encoding genes; a polysaccharide gene cluster (epa) that appears to influence virulence in mice; different adherence phenotypes, and a gene, ace, that appears to be involved in adherence; and a gene locus with homology to the accessory gene regulator (agr) locus of staphylococci that is involved in expression of an E. faecalis gelatinase and a serine protease that also influence virulence in mice. In this application, the investigators propose (1) to verify that the E. faecalis agr-like locus regulates gelE and sprE and determine if all are important for virulence; to investigate the distribution of these genes among E. faecalis; and to determine how the enterococcal agr-like locus is regulated and if it, like the staphylococcal agr, regulates other genes. They also plan (2) to test the hypothesis that Ace (a newly described adhesin for collagen of enterococci) is the cause of the adherence we have reported and is important for virulence; to explore the regulation of Ace production; and to determine the distribution and effect of variations in ace, if Ace elicits an antibody response in humans (using recombinant Ace and patient sera) infected by E. faecalis and if antibody made during infection, or antibody to recombinant Ace, is protective. In their third specific aim, they plan (3) to establish if the polysaccharide gene cluster is the cause of a recently described mucoid phenotype, to study its regulation, and to further test its contribution to adherence to foreign material, virulence and protection. They will also explore a system for constructing non-polar deletion mutants using counter-selection based on their prior work with the E. faecalis pyr genes, and to explore additional assays that would help to avoid lethality models. The investigators hope that results from this work will provide solid leads in the quest for methods to prevent, control, or combat E. faecalis infections.