Molecular interactions: oral bacteria & matrix proteins

描述：伴生放线杆菌是一种革兰氏阴性的兼性厌氧细菌，在人类口腔和上呼吸道定植。这种细菌与局限性侵袭性牙周炎(LAP)和成人牙周炎密切相关。这种病原体是其他严重感染的病原体，包括感染性心内膜炎、软组织脓肿和肺炎，并可能导致心血管疾病。牙周组织被认为是这些非口腔疾病的来源，但对伴生放线菌在口腔中定植以及在组织中渗透和传播的趋向性知之甚少。病原体已经制定了不同的策略来成功地在宿主组织上定植。这些病原体的一个共同主题是，在严酷或恶劣的条件下，通过与特定宿主大分子的黏附来启动感染的能力。这些分子包括宿主细胞分泌的形成细胞外基质(ECM)的蛋白质。伴生放线菌存在于牙周组织的结缔组织中，并与感染组织中的胶原纤维密切相关。细菌还与细胞外基质蛋白、胶原、纤维连接蛋白和层粘连蛋白结合。利用遗传学方法，我们已经鉴定出第一个伴随放线菌的胶原粘附素、EMA(细胞外基质蛋白粘附素)A和多个参与调控ECM蛋白粘附素活性表达的基因。EmaA在结构上与YADA相关，YADA是肠道致病耶尔森菌的一种多用途ECM蛋白粘附素。为了阐明EMAA在细菌定植和致病中的作用，我们建议1)从细胞定位和胶原结合的角度研究EMAA的蛋白结构域，2)研究与EMAA相关的表面结构和该蛋白的体外毒力潜力，3)在大鼠心内膜炎和小鼠牙周炎模型中测定EMAA的体内毒力。这项拟议研究的长期目标是识别和表征口腔和非口腔组织定植所需的细菌粘附素。这些粘附素可能成为未来药物开发的靶点，涉及破坏宿主-病原体相互作用的小分子或疫苗。

DESCRIPTION: Actinobacillus actinomycetemcomitans is a Gram-negative, facultative anaerobic bacterium that colonizes the human oral cavity and the upper respiratory tract. This bacterium is strongly associated with localized aggressive periodontitis (LAP) and with cases of adult periodontitis. This pathogen is the causative agent for other serious infections including infectious endocarditis, soft tissue abscesses, and pneumonia and may contribute to cardiovascular disease. The periodontium is believed to be the source for these non-oral diseases, but little is known about the tropism used by A. actinomycetemcomitans to colonize the oral cavity and to infiltrate and disseminate in tissues. Pathogens have developed diverse strategies to be successful in colonization of host tissues. A common theme amongst these pathogens is the ability to initiate infection by adhesion to specific host macromolecules under stringent or hostile conditions. These molecules include proteins secreted by host cells that form the extracellular matrix (ECM). A. actinomycetemcomitans is found in the connective tissue of the periodontium and in close association with collagen fibers in infected tissues. The bacterium also binds to the ECM proteins, collagen, fibronectin and laminin. Using a genetic approach, we have identified the first A. actinomycetemcomitans collagen adhesin, Ema (extracellular matrix protein adhesin)A and multiple genes involved in regulating the expression of ECM protein adhesin activity. EmaA is structurally related to YadA, a multipurpose ECM protein adhesin of the enteropathogenic bacterium Yersinia enterocolitica. To elucidate the role of EmaA in colonization and pathogenicity of the bacterium, we propose to 1) investigate the protein domains of EmaA in terms of cellular localization and collagen binding, 2) investigate the surface structures associated with EmaA and the in vitro virulence potential of this protein, and 3) determine the in vivo virulence of emaA in a rat endocarditis and mouse periodontitis model. A long term goal of the proposed research is to identify and characterize bacterial adhesins that are required for the colonization of the oral cavity and non-oral tissues. These adhesins may serve as targets for future drug development involving small molecules or vaccines that disrupt host-pathogen interactions.