Tight Adherence Genes of a Periodontal Pathogen

牙周病原体的紧密粘附基因

基本信息

批准号：
6930582
负责人：
DAVID H FIGURSKI
金额：
$ 39.06万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-01 至 2007-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The Gram-negative bacterium, Actinobacillus actinomycetemcomitans, is believed to be the etiologic agent for localized juvenile periodontitis (LJP), a particularly destructive disease in adolescents. The incidence of LJP varies among demographic groups and disproportionately burdens minorities and the poor. A. actinomycetemcomitans has been associated with a variety of other infections, notably brain abscesses, and it is a member of the clinically important HACEK group of bacteria implicated in infective endocarditis. A striking characteristic of fresh clinical isolates of A. actinomycetemcomitans is their ability to form extremely tenacious biofilms, a property thought to be critical for colonization of teeth and other surfaces. Molecular genetic studies in this laboratory have revealed that the genome of A. actinomycetemcomitans maintains a cluster of tad genes required for tight adherence to surfaces. The studies indicate that the tad genes are part of a locus of 14 genes encoding a novel secretion system for the assembly and release of long, bundled FIp fibrils and that the fibrils are required for tight nonspecific adherence to surfaces and bacterial autoaggregation. Remarkably similar tad-like loci were subsequently found in the genome sequences of a wide variety of Gram-negative and Gram-positive Bacteria, including many significant pathogens, and in Archaea. Given the clear requirement of the tad gene cluster for adherence of A. actinomycetemcomitans, the tad loci in other organisms are likely to be important for microbial colonization in a variety of environmental niches. Proposed here are molecular and genetic studies of the tad locus of A. actinomycetemcomitans. The objectives are the following: 1) to understand the mechanisms of expression and regulation of the genes of the tad locus; and 2) to determine the locations, interactions, and molecular functions of the gene products in secretion and fibril assembly. These studies are expected to lead to a basic understanding of a novel secretion system of bacteria and its role in the biogenesis of fibrils required for tight adherence and colonization by A. actinomycetemcomitans. Since of the widespread nature of the tad loci, these studies should also lead to new insights into colonization by other bacterial pathogens and may serve to identify new targets for development of antibiotics.

描述（由申请人提供）：革兰氏阴性细菌，Actinobacillus actinomycetemcomitans，被认为是局部青少年牙周炎（LJP）的病原体，LJP是青少年中一种特别具有破坏性的疾病。 LJP 的发病率因人口群体而异，对少数族裔和穷人造成不成比例的负担。伴放线放线菌与多种其他感染有关，特别是脑脓肿，它是与感染性心内膜炎有关的临床上重要的 HACEK 细菌群的成员。伴放线放线菌的新鲜临床分离株的一个显着特征是它们能够形成极其顽强的生物膜，这种特性被认为对于牙齿和其他表面的定植至关重要。该实验室的分子遗传学研究表明，A. actinomycetemcomitans 的基因组保留了紧密粘附在表面所需的一组 tad 基因。研究表明，tad 基因是 14 个基因座的一部分，这些基因编码一种新的分泌系统，用于组装和释放长的、成束的 FIp 原纤维，并且这些原纤维是紧密非特异性粘附在表面和细菌自动聚集所必需的。随后在多种革兰氏阴性和革兰氏阳性细菌（包括许多重要病原体）和古细菌的基因组序列中发现了非常相似的 tad 样基因座。鉴于 tad 基因簇对 A. actinomycetemcomitans 粘附的明确要求，其他生物体中的 tad 位点可能对于各种环境生态位中的微生物定殖很重要。这里提出了 A. actinomycetemcomitans 的 tad 基因座的分子和遗传学研究。目标如下：1）了解tad基因座基因的表达和调控机制； 2) 确定基因产物在分泌和原纤维组装中的位置、相互作用和分子功能。这些研究有望使人们对细菌的新型分泌系统及其在伴放线放线菌紧密粘附和定殖所需的原纤维生物发生中的作用有一个基本的了解。由于 tad 位点的广泛性，这些研究还应该对其他细菌病原体的定植产生新的见解，并可能有助于确定抗生素开发的新靶标。