VIRULENCE IN ENTEROAGGREGATIVE E COLI

肠聚集性大肠埃希菌(EAEC)是一种日益公认的人类腹泻病原体。这种细菌与发展中国家和工业化国家的零星腹泻、发展中国家艾滋病患者和儿童的持续性腹泻综合症、旅行者腹泻以及各种腹泻暴发有关。PI发现了这种致泻性大肠杆菌，并在描述这种微生物的发病机制和流行病学方面处于领先地位，这是我们在EAEC感染发病机制方面的基础工作的竞争性延续。总体而言，我们的目标是促进对EAEC发病机制的了解，更好地定义真正的EAEC病原体，改进诊断方法，并识别保护性免疫原。这项提议的三个目标力求扩大本奖项资助的工作中最重要和最有希望的方面。目的1：EAEC的黏附-聚集特性是EAEC的定义特性。我们的观察表明，聚集粘连(AA)是生物膜形成的前奏，生物膜在体内发生，可以在体外模拟。在这一目标中，我们将进一步阐明EAEC遵守的基本方面。目的2：EAEC毒力的调节-AggR是一种高度流行和保守的AAF表达激活剂。然而，对EAEC毒力的调控尚不清楚。从AggR开始，我们将扩大对EAEC基因调控的研究。目的3：重建EAEC-我们将使用体外器官培养和EAEC感染的T84细胞模型来回答这样一个问题：哪些基因是必要和充分的，才能赋予我们观察到的效果？该奖项下的工作将极大地促进EAEC目前的知识状况，并将导致对致病机制、诊断试剂和候选疫苗的识别。

Enteroaggregative Escherichia coli (EAEC) is an increasingly recognized pathogen of human diarrhea. This organism has been implicated in sporadic diarrhea in developing and industrialized countries, in the persistent diarrhea syndrome in AIDS patients and children in the developing world, in traveler's diarrhea, and in various diarrheal outbreaks. The PI discovered this pathotype of diarrheagenic E. coli and has been the leader in describing the pathogenesis and epidemiology of this organism, This is a competing continuation of our fundamental work on the pathogenesis of EAEC infection. Overall, our objectives are to advance knowledge of EAEC pathogenesis, to better define true EAEC pathogens, to refine diagnostic methods and to identify protective immunogen. The three aims of this proposal seek to extend the most important and promising aspects of the work funded under the current award. Aim 1: Characterization of EAEC adhesion-Aggregation is the defining characterization of EAEC. Our observations suggest that aggregative adherence (AA) is a prelude to biofilm formation, which occurs in vivo and which can be modeled in vitro. In this aim, we will further elucidate fundamental aspects of EAEC adherence. Aim 2: The Regulation of EAEC virulence- AggR is a highly prevalent and conserved activator of AAF expression. However, nothing else is known of the regulation of EAEC virulence. Beginning with AggR, we will expand our studies of EAEC gene regulation. Aim 3: Reconstructing EAEC-We will use in vitro organ culture and T84 cell models of EAEC infection to answer the question: what genes are necessary and sufficient to confer the effects that we observe? The work under this award will greatly advance the current state of knowledge of EAEC and will result in the identification of pathogenetic mechanisms, of diagnostic reagents and in vaccine candidates.