Molecular Interactions: Oral Bacteria & Matrix Proteins

分子相互作用：口腔细菌

• 批准号: 7637408
• 负责人: KEITH Peter MINTZ
• 金额: $ 34.67万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637408
• 关键词: Abscess; Actinobacillus actinomycetemcomitans; Adhesions; Adult; Amino Acid Sequence; Anaerobic Bacteria; Antibodies; Bacteria; Bacterial Adhesins; Binding; Binding Proteins; Biological; C-terminal; Cardiovascular Diseases; Cell surface; Cells; Chronic; Collagen; Collagen Fiber; Communicable Diseases; Complex; Connective Tissue; Development; Disease; Disease Progression; Elements; Endocarditis; Epitopes; Extracellular Matrix; Extracellular Matrix Proteins; Fibrillar Collagen; Fibronectins; Future; Genes; Genetic; Gingiva; Goals; Gram-Negative Anaerobic Bacteria; Head; Human; Immune response; Immunoelectron Microscopy; Infection; Inflammatory; Laminin; Maps; Mediating; Membrane; Molecular; Mouth Diseases; N-terminal; Neck; Oral; Oral cavity; Pathogenicity; Peptide Signal Sequences; Peptides; Periodontal Diseases; Periodontitis; Periodontium; Phase; Pneumonia; Positioning Attribute; Proteins; Regulation; Research; Resistance; Role; Source; Structure; Surface; Testing; Tissues; Transmembrane Domain; Transmission Electron Microscopy; Tropism; Upper respiratory tract; Vaccines; Variant; Vesicle; Virulence Factors; Yersinia enterocolitica; antimicrobial; appendage; bactericide; base; drug development; insight; macromolecule; mutant; novel; novel therapeutics; oral bacteria; oral tissue; pathogen; pathogenic bacteria; prevent; small molecule; soft tissue

DESCRIPTION (provided by applicant): 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, 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, and is associated with bacterial cell surface appendages. These EmaA structures are proposed to be fundamental for collagen adhesion. To elucidate the role of EmaA in colonization and pathogenicity of the bacterium, we propose to 1) map the functional domains of EmaA by determining the collagen binding, subcellular localization, and assembly of surface structures in A. actinomycetemcomitans, 2) investigate the surface structures associated with EmaA by transmission electron microscopy and the role of these structures in resistance to the innate immune response of the host, and 3) determine the number of EmaA molecules required for the assembly of structures on the surface of A. actinomycetemcomitans. 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. Lay statement: Binding to host tissues is the initial phase of all infectious diseases. Understanding how bacteria interact with host cells or tissue constituents will aid in the development of novel therapeutics to prevent initiation or progression of the disease.

描述（由申请人提供）：放线放线杆菌是一种革兰氏阴性、兼性厌氧细菌，定植于人类口腔和上呼吸道。这种细菌与局部侵袭性牙周炎 (LAP) 和成人牙周炎病例密切相关。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、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根源，但对于伴放线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。病原体已经发展出多种策略来成功地在宿主组织中定殖。这些病原体的一个共同主题是能够在严格或敌对条件下通过粘附到特定宿主大分子来引发感染。这些分子包括由形成细胞外基质（ECM）的宿主细胞分泌的蛋白质。伴随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。该细菌还与 ECM 蛋白、胶原蛋白、纤连蛋白和层粘连蛋白结合。使用遗传方法，我们鉴定了第一个 A. actinomycetemcomitans 胶原粘附素、Ema（细胞外基质蛋白粘附素）A 和多个参与调节 ECM 蛋白粘附素活性表达的基因。 EmaA 在结构上与 YadA 相关，YadA 是肠病原细菌小肠结肠炎耶尔森氏菌的一种多用途 ECM 蛋白粘附素，并且与细菌细胞表面附属物相关。这些 EmaA 结构被认为是胶原蛋白粘附的基础。为了阐明 EmaA 在细菌定植和致病性中的作用，我们建议 1) 通过确定 A. actinomycetemcomitans 中的胶原蛋白结合、亚细胞定位和表面结构组装来绘制 EmaA 的功能域图，2) 研究表面结构通过透射电子显微镜与 EmaA 相关联，以及这些结构在抵抗宿主先天免疫反应中的作用，以及 3) 确定结构组装所需的 EmaA 分子数量在 A. actinomycetemcomitans 的表面。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。这些粘附素可以作为未来药物开发的目标，涉及破坏宿主与病原体相互作用的小分子或疫苗。外行声明：与宿主组织结合是所有传染病的初始阶段。了解细菌如何与宿主细胞或组织成分相互作用将有助于开发新的疗法来预防疾病的发生或进展。