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（由申请方提供）：伴放线放线杆菌是一种革兰氏阴性兼性厌氧菌，定植于人体口腔和上呼吸道。这种细菌与局限性侵袭性牙周炎（牙周炎）和成人牙周炎病例密切相关。该病原体是其他严重感染的病原体，包括感染性心内膜炎、软组织水肿、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来源，但对A.放线菌共生菌在口腔中定植，并在组织中浸润和扩散。病原体已经发展了不同的策略来成功地在宿主组织中定殖。在这些病原体中的一个共同主题是在严格或不利条件下通过粘附于特定宿主大分子而引发感染的能力。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。A.伴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。细菌还结合ECM蛋白质、胶原蛋白、纤连蛋白和层粘连蛋白。利用遗传学方法，我们已经确定了第一个A。伴随放线菌胶原粘附素、Ema（细胞外基质蛋白粘附素）A及多个基因参与调节ECM蛋白粘附素活性的表达。EmaA在结构上与YadA相关，YadA是肠致病性细菌小肠结肠炎耶尔森氏菌的多用途ECM蛋白粘附素，并且与细菌细胞表面附属物相关。这些EmaA结构被认为是胶原粘附的基础。为了阐明EmaA在细菌定殖和致病性中的作用，我们提出：1）通过确定A.放线菌共生体，2）研究表面结构与EmaA通过透射电子显微镜和这些结构的作用，在抵抗宿主的先天免疫反应，和3）确定的EmaA分子的数量所需的组装结构上的表面A。伴放线菌拟议研究的长期目标是鉴定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靶点，涉及破坏宿主-病原体相互作用的小分子或疫苗。外行陈述：与宿主组织结合是所有感染性疾病的初始阶段。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治疗方法，以防止疾病的发生或进展。