Long Polar Fimbriae of Attaching and Effacing Escherichia coli

附着和消除大肠杆菌的长极菌毛

• 批准号: 7846683
• 负责人: Alfredo G Torres
• 金额: $ 2.01万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846683
• 关键词: AT Rich Sequence; Adhesions; Animal Model; Bacterial Adhesins; Bacteriophages; Biological Products; Categories; Cells; Collaborations; Country; DNA; Data; Diagnostic; Diagnostic tests; Diarrhea; Disease; Enterocytes; Environment; Escherichia coli; Escherichia coli EHEC; Escherichia coli Infections; Escherichia coli O157; Evolution; Family; Fimbrial Adhesins; Food Safety; Funding; Gastrointestinal tract structure; Gene Cluster; Genes; Genetic; Goals; Hemolytic-Uremic Syndrome; Human; In Vitro; Infant; Infantile Diarrhea; Infection; Infectious Diseases Research; Interdisciplinary Study; International; Intestines; Investigation; Knowledge; Lesion; Letters; Link; Mediating; Mobile Genetic Elements; Modeling; Organism; Oryctolagus cuniculus; Outcome; Pathogenesis; Pathogenicity Island; Plasmids; Play; Prevalence Study; Process; Production; Promoter Regions; Property; Proteins; Regulation; Research; Research Personnel; Resources; Role; Staging; System; Testing; Therapeutic; Therapeutic Uses; Virulence; Virulence Factors; Virulent; Work; base; enteropathogenic Escherichia coli; fimbria; genetic regulatory protein; genome sequencing; human disease; improved; in vivo; innovation; insight; novel; novel therapeutics; pathogen; pathogenic Escherichia coli; pathogenic bacteria; prevent; prototype; public health relevance; research study; tissue tropism

DESCRIPTION (provided by applicant): The expression of Attaching and Effacing Escherichia coli (AEEC) virulence factors is a tightly regulated process, and, in some cases, the identification of these factors has been difficult because they are either repressed in vitro or the conditions of expression are unknown. While it is evident that expression of certain virulence factors is strictly associated with human disease, the additional factors present in AEEC strains that are linked to their pathogenic process remain unclear. Lack of a full understanding of how the genes encoding these additional virulence factors are controlled is important, because, without this knowledge, we are unlikely to understand the overall pathogenic properties of AEEC strains. Thus, our objective is to determine how the Long Polar (LP) fimbriae in AEEC strains contribute to pathogenesis and to use these fimbrial-encoding genes as markers to detect virulent strains. The central hypothesis is that, in addition to the already characterized colonization factors (e.g., intimin-mediated adhesion), AEEC strains possess a highly regulated LP fimbriae, that plays a role in the colonization process, and although the genes encoding these fimbriae are widely distributed in pathogenic E. coli strains, some LP fimbriae types are found exclusively in specific AEEC strains. We will test this hypothesis through three specific aims, which are to: 1) Define whether Ler and H-NS act as a selective silencing/anti-silencing defense system that controls LP fimbriae expression in AEEC strains; 2) Identify the regulatory protein(s) controlling LP fimbriae expression in atypical EPEC and determine in a rabbit model the function of LP fimbriae during colonization; and 3) Characterize the distribution of the LP fimbrial gene clusters among AEEC strains and determine whether certain LP fimbrial subunit types are reliable markers of different pathogenic AEEC strains. To accomplish our aims, we will fully characterize the functions of Ler, H-NS, and atypical enteropathogenic E. coli-encoded regulators under in vitro and in vivo (infant rabbit colonization model) conditions and perform a detailed study of prevalence of the lpf genes in specific subsets of pathogenic AEEC strains. Our research work is innovative because it capitalizes on our findings regarding novel colonization factors in AEEC strains and their potential application in therapeutics and diagnostics. The results from studies of the regulatory networks controlling LP fimbriae expression have significance, because we will be able to identify fundamental differences to explain the tissue tropism of different AEEC strains and to determine whether silencing of LP fimbriae is an example of a defense system that AEEC strains have against horizontally acquired genes. In addition, the use of the rabbit model will give us new insight into the pathogenesis and colonization properties of AEEC strains. An understanding of the mechanisms underlying AEEC colonization to the gastrointestinal tract will not only further our knowledge of the pathogenesis of these organisms but also provide opportunities for reducing infection rates and improving treatment options against these biological agents classified as category B pathogens due t their potential use as a food safety threat. PUBLIC HEALTH RELEVANCE: Attaching and effacing Escherichia coli (AEEC) represent a diverse group of isolates implicated in diarrhea in humans in several countries. Most AEEC strains possess highly regulated Long Polar (LP) fimbriae, which contribute to the intestinal colonization process of some of the AEEC isolates. Their full characterization will provide new and deeper insights into the process of AEEC colonization, and a better understanding of their regulatory mechanisms controlling expression, which will be a basis for developing novel therapeutics and simplified diagnostic tests

描述（由申请人提供）：附着和排出的大肠杆菌（AEEC）毒力因子的表达是一个严格调节的过程，在某些情况下，这些因素的鉴定很困难，因为它们在体外受到抑制，或者表达状况尚不清楚。虽然很明显，某些毒力因子的表达与人类疾病严格相关，但与其致病过程有关的AEEC菌株中存在的其他因素尚不清楚。缺乏对编码这些附加毒力因子的控制的基因的全面了解很重要，因为在没有这些知识的情况下，我们不太可能了解AEEC菌株的总体病原体特性。因此，我们的目标是确定AEEC菌株中的长极（LP）纤维如何有助于发病机理，并将这些纤维化编码基因作为标记来检测有毒菌株。中心假设是，除了已经具有特征性的定殖因子（例如，内膜素介导的粘附）外，AEEC菌株还具有高度调节的LP纤维菌，在定殖过程中起着作用，尽管这些基因编码这些fimbriae的基因在致病的E. coli coli中均分布在病原上，但在某些lp sTrains inter inters inter typers in typers in typers in lp a in lp a in lp inter inter inter inter inter in lp a in lp a in lp s of lp imbria in lp a in lp s of lp imbria in lp inter in lp inter in lp interec。我们将通过三个特定目的来检验这一假设，它们是：1）定义LER和H-NS是否充当选择性的沉默/反沉降防御系统，该系统控制AEEC菌株中LP Fimbriae的表达； 2）确定在非典型EPEC中控制LP Fimbriae表达的调节蛋白，并在兔模型中确定LP纤维化在定殖过程中的功能； 3）表征LP纤维化基因簇在AEEC菌株中的分布，并确定某些LP纤维亚基类型是否是不同致病性AEEC菌株的可靠标记。为了实现我们的目标，我们将充分表征LER，H-NS和非典型肠发病大肠杆菌coli coli coli coli coni-Socultation在体外和体内（婴儿兔子定殖模型）条件下的功能，并对患病AEEC菌株的特定亚基中LPF基因的流行进行详细研究。我们的研究工作具有创新性，因为它利用了我们关于AEEC菌株中新殖民因素的发现及其在治疗和诊断中的潜在应用。控制LP Fimbriae表达的调节网络的研究的结果具有显着性，因为我们将能够识别基本差异，以解释不同AEEC菌株的组织对流，并确定LP Fimbriae的沉默是否是AEEC菌株对AEEC菌株的示例是否抗空基因。此外，兔模型的使用将使我们对AEEC菌株的发病机理和定植特性有了新的见解。了解对胃肠道的AEEC定殖基于的机制的理解不仅会进一步了解我们对这些生物的发病机理的了解，而且还为降低感染率和改善对这些归类为B类病原体的生物学剂的治疗选择的机会提供了机会，因为它们的潜在用途是食品安全威胁。公共卫生相关性：附加和esd escherichia coli（AEEC）代表了多种多样的孤立物，涉及几个国家的人类腹泻。大多数AEEC菌株具有高度调节的长极（LP）纤维膜，这有助于某些AEEC分离株的肠道定植过程。它们的完整表征将为AEEC定植过程提供更深入的深入了解，并更好地理解其控制表达的调节机制，这将是开发新型治疗和简化诊断测试的基础