REGULATION OF EXPRESSION OF ADHERENCE FACTORS

描述(改编自调查摘要)：产肠毒素 大肠埃希氏菌(ETEC)是导致婴儿腹泻的主要原因 以及小孩子和旅行者。建立的第一步是 感染是病原体附着在宿主组织上，这是 据信由菌毛(和/或更薄、更有弹性的纤维)介导 结构)。这项工作的主要长期目标是理解 菌毛的合成机制及其调控机制 它们的合成。 少数血清学上不同的菌毛似乎是流行的。 从人类疾病中分离的ETEC菌株中。其中包括CS1和 CS2，以及CFA/I(似乎是 相似，基于DNA序列)、CS4和CS5。 合成人ETEC菌毛所需的基因完全是 与研究较好的E. 大肠杆菌菌毛与纸和1型菌毛相似。CS1菌毛似乎简单得多 结构，所以对它们的详细理解似乎是可能的 形态发生是触手可及的。本提案的目标1和2是针对 在处理这个问题上。(目的1：鉴定CS1菌毛的形态发生 通过确定每个基因产物在菌毛组装和目的中的作用 2：描述菌毛组装和黏附过程中的蛋白质相互作用。) CS1和CS2受RNS正向调节，与 Arac，以及许多肠道致病决定因素的全球调节因子 病原体。RNS同源似乎是表达许多 不同血清型肠出血性肠出血性肠杆菌菌毛 致泻性大肠杆菌菌株。目前的信息表明， RNS对和的表达的调节是不寻常的，涉及DNA区域 在受调控启动子的上游和下游。此外，它还 可能涉及一连串的监管因素。因此，因为它可能 说明了基因控制的新原理，因为它很可能 CS1在细菌发病机制、表达调控中的重要作用 PILI将被进一步分析。(目标3：确定 RNS的监管和目标4：调查CS1的其他监管。) PILI似乎是开发人类抗ETEC的良好候选者 疫苗，因为它们的血清变异性有限，以及 它们的表面定位和免疫原性，并因为成功 国内菌毛疫苗在预防腹泻疾病中的应用 动物。这项工作应有助于此类疫苗的开发。

DESCRIPTION (adapted from investiators abstract): Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrheal disease in infants and small children and in travelers. The first step in establishment of infection is attachment of the pathogen to the host tissue, which is believed to be mediated by pili (and/or thinner, more flexible fibrillar structures). The major long-term goals of this work are to understand the mechanisms by which pili are synthesized and the mechanisms that regulate their synthesis. A limited number of serologically different pili appear to be prevelant among ETEC strains isolated from human disease. These include CS1 and CS2, studied in this project, as well as Cfa/I (which appears to be similar, based on DNA sequence), CS4 and CS5. The genes needed for synthesis of human ETEC pili are completely unrelated to those identified for morphogenesis of the better studied E. coli pili like pap and type 1. CS1 pili appear to be much simpler structures, so it seems possible that a detailed understanding of their morphogenesis is within reach. Aims 1 and 2 of this proposal are directed at approaching this. (aim 1: Characterize the morphogenesis of CS1 pili by determining the role of each gene product in pilus assembly and Aim 2: Characterize protein interactions in pilus assembly and adherence.) CS1 and CS2 are positively regulated by Rns, which shows homology to AraC, as do global regulators of virulence determinants of many enteric pathogens. A Rns homolog seems to be necessary for expression of many different serological types of ETEC pili, as well as pili of other diarrheagenic E. coli strains. Current information indicates that regulation of expression of and by Rns is unusual, involving DNA regions both upstream and downstream of the regulated promoter. In addition, it may involve a cascade of regulatory factors. Thus, because it may illustrate new principles of control of gene and because it is likely to be important for bacterial pathogenesis, regulation of expression of CS1 pili will be analyed further. (Aim 3: Determine the mechanism of regulation by rns and Aim 4: Investigate other regulation of CS1.) Pili appear to be good candidates for development of human anti-ETEC vaccines because of their limited serological variability, as well as their surface localiztion and immunogenicity, and because of the success of pili based vaccines in prevention of diarrheal diseases in domestic animals. This work should facilitate the development of such vaccines.