Novel clone-specific virulence determinants of A. actinomycetemcomitans

描述(申请人提供)：伴生放线杆菌(AA)是牙周炎多菌感染的主要病原体。不同的AA克隆谱系的定植可能会导致不同的后果，从轻微的疾病到侵袭性牙周炎的发展。AA毒力变化的基础尚不完全清楚，这对AA相关性牙周炎的有效诊断和治疗提出了挑战。AA在基因含量上表现出显著的差异，主要是因为已知的与细菌毒力潜力相关的基因组岛。我们研究计划的长期目标是确定AA毒力决定因素的全谱。为了达到这个目标，这项研究的目的是确定基因组岛在牙周炎中A的发病机制中的作用。核心假设是AA的毒力受基因组岛的调控，由Th17细胞介导，并被Treg抵消。这一假说是基于对171个AA基因组岛的初步研究提出的，这些研究表明：(I)特定岛基因的疾病关联，(Ii)某些仅限于高毒力AA株的岛基因的分布，(Iii)单个岛基因与其他病原体的已知毒力因子的同源性，以及(Iv)岛基因的表达模式，表明其具有功能性。本研究将致力于以下两个方面的研究：1.AA基因组岛的体外功能分析。工作假设是基因组岛在体内类似的条件下表达，并调节AA的毒力表达。目的2.在体内表征基因组岛对AA毒力的作用。工作假说是基因组岛通过Th17和调节性T细胞免疫反应调节AA在牙周炎中的毒力；前者导致骨溶解和组织破坏，而后者抑制炎症反应。这一假设将通过一种新的大鼠动物模型进行验证。这些概述的研究将首次评估和鉴定与AA毒力相关的基因组岛，并揭示其致病机制。这一结果有望产生重要的积极影响，因为这些信息将扩大对再障发病机制的认识，从而改善牙周感染的诊断和治疗。 公共卫生相关性：这项拟议的研究与NIDCR的使命相关，即“通过研究改善口腔健康……”因为伴生放线杆菌(AA)是牙周炎的主要病原学。我们的长期目标是确定AA病毒素决定因素的全谱。这一结果将改善该病的诊断和治疗。1

DESCRIPTION (provided by applicant): Aggregatibacter actinomycetemcomitans (Aa) is a key pathogen in the polymicrobial infection of periodontitis. Colonization by distinct clonal lineages of Aa may lead to different consequences, from minimal diseases to the development of aggressive periodontitis. The basis for the variable virulence of Aa is not fully understood, an presents a challenge to effective diagnosis and management of Aa-associated periodontitis. Aa demonstrates significant variation in gene content primarily because of genomic islands, which have been known to be associated with bacterial virulence potential. The long-term goal of our research plan is to identify the full spectrum of the virulence determinants of Aa. Toward that goal, the objective of this study is to define the role of genomic islands in the pathogenesis of A in periodontitis. The central hypothesis is that the virulence of Aa is modulated by genomic islands and mediated by Th17 cells and counteracted by Treg. The hypothesis is formulated based on the preliminary studies of the 171 Aa genomic islands that demonstrated (i) disease-association of specific island genes, (ii) distribution of some island genes limited to Aa strains f high virulence, (iii) homology of individual island genes to known virulence factors of other pathogens, and (iv) patterns of expression of the island genes that suggested functionality. Two aims will be pursued: Aim 1. In vitro functional analysis of genomic islands of Aa. The working hypothesis is that genomic islands are expressed in in vivo like conditions and modulate the virulence expression of Aa. Aim 2. In vivo characterization of the role of genomic islands to Aa virulence. The working hypothesis is that the genomic islands modulate the virulence of Aa in periodontitis via Th17 and regulatory T cell immune responses; the former leads to osteolysis and tissue destruction, while the latter dampens the inflammatory response. The hypothesis will be tested with a novel animal model of rats. The outlined studies will for the first time evaluate and identify virulence-associated genomic islands of Aa and reveal their pathogenic mechanisms. The results are expected to have an important positive impact, because the information will expand the knowledge to the pathogenesis of Aa leading to improved diagnostics and treatment of periodontal infections. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to the NIDCR's mission "to improve oral health...through research..." because A. actinomycetemcomitans (Aa) is a major etiology of periodontitis. Our long-term goal is to identify the full spectrum of the virulene determinants of Aa. The results will lead to improved diagnostics and treatment of the disease. 1