Novel clone-specific virulence determinants of A. actinomycetemcomitans

A. actinomycetemcomitans 的新型克隆特异性毒力决定因素

• 批准号: 8371620
• 负责人: Casey CHEN
• 金额: $ 43.29万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371620
• 关键词: Actinobacillus actinomycetemcomitans; Animal Model; Bacteria; Cells; Complex; Data; Development; Diagnosis; Diagnostic; Disease; Disease Association; Environment; Etiology; Gene Expression; Genes; Genomic Islands; Genomics; Goals; Growth; Immune response; Implant; In Vitro; Individual; Infection; Inflammation Mediators; Inflammatory Response; Investigation; Island; Knowledge; Lead; Mediating; Mediator of activation protein; Microbial Biofilms; Mission; Modeling; Mucous Membrane; Oral health; Osteolysis; Osteolytic; Outcome; Pathogenesis; Pattern; Periodontal Infection; Periodontitis; Rattus; Regulatory T-Lymphocyte; Research; Role; Simulate; T cell response; T-Lymphocyte; Testing; Time; Tissues; Validation; Variant; Virulence; Virulence Factors; Work; base; bone loss; cytokine; design; fitness; improved; in vivo; mutant; novel; novel diagnostics; novel therapeutic intervention; pathogen; peri-implantitis; response

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

描述（申请人提供）：放线菌群（Aa）是牙周炎多微生物感染的关键病原体。不同克隆系Aa的定植可能导致不同的后果，从轻微疾病到侵袭性牙周炎的发展。Aa不同毒力的基础尚不完全清楚，这对Aa相关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，主要是因为基因组岛，而基因组岛已知与细菌毒力潜力有关。我们研究计划的长期目标是确定Aa毒力决定因素的全谱。为了实现这一目标，本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的毒力由基因组岛调节，Th17细胞介导，Treg细胞抵消。这一假设是根据对171个Aa基因组岛的初步研究提出的，这些研究表明：(i)特定岛基因与疾病有关，（ii）一些岛基因的分布仅限于高毒力Aa菌株，（iii）个别岛基因与其他病原体已知毒力因子的同源性，以及（iv）表明功能的岛基因的表达模式。将实现两个目标：目标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条件下表达并调节Aa的毒力表达。目标2。基因组岛对Aa毒力作用的体内表征。目前的假设是，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，而后者则抑制炎症反应。这一假设将用一种新的大鼠动物模型进行验证。概述的研究将首次评估和鉴定Aa的毒力相关基因组岛，并揭示其致病机制。这一结果将对牙周感染的诊断和治疗产生重要的积极影响，因为该信息将扩大对牙周感染发病机制的了解。