VARIANT STREPTOCOCCI FROM ENDOCARDITIS

心内膜炎变异链球菌

• 批准号: 3341137
• 负责人: IVO J VAN DE RIJN
• 金额: $ 14.51万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-08-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3341137
• 关键词: Streptococcus mitis; adhesin; antibacterial antibody; bacterial antigens; bacterial endocarditis; bacterial proteins; bactericidal immunity; carbohydrate sequence; cell wall; chemical structure function; extracellular matrix; gene mutation; genetic strain; heart valves; host organism interaction; human tissue; immunochemistry; laboratory mouse; laboratory rabbit; laboratory rat; molecular cloning; nuclear magnetic resonance spectroscopy; protein purification

Subacute bacterial endocarditis is a serious disease which accounts for 0.3-3.0/1000 of all hospital admissions and the viridans streptococci remain the most frequent cause of bacterial endocarditis. Since 1961 a new group of organisms were recognized, the nutritionally variant streptococci, which cause approximately 5-10% of all cases of streptococcal endocarditis. The NVS are important pathogens of bacterial endocarditis since patients present with a higher degree of antimicrobial failure, relapse and fatality than other forms of viridans endocarditis. The overall objective of the research program is to continue a systematic study of the surface components of nutritionally variant streptococci (NVS) in order to better understand the interaction of these bacteria with the heart valves in infective subacute bacterial endocarditis. Toward this objective we plan to: 1. Complete the structural analysis of the Streptococcus defectivus and Streptococcus adjacent group antigens. 2. Determine the identity of the S. defectivus adhesion(s) responsible far the adherence of the organisms to extracellular matrix. Isolate and purify the adhesion by standard purification protocols (monoclonal antibody and affinity chromatography, hydrophobic, ion exchange, gel permeation chromatography) and/or molecular cloning (lambda gtll or cosmid libraries). 3. Identify the binding domain on the adhesion (peptide inhibition studies and specific removal of anti-adhesion antibody) and the corresponding extracellular matrix receptor(s) responsible for adherence of S. defectivus strains (photoreactive cross- linking studies, monoclonal antibodies, immunoblots). 4. Determine the role of the adhesion(s) in protection against S. defectivus endocarditis. The rat endocarditis model will be used to analyze the role of the adhesion in initiation of endocarditis. Transposon-inactivation and\or nitrous acid deletion mutants also will be compared to parent strains in the model. Finally the role of anti-adhesion antibody will be determined in protection against NVS endocarditis. The specific aims commence with a structural and immunochemical analysis of the surface components of these strains and end with the study of their structure-function relationship in the attachment to and colonization of the heart valve, a primary step in the pathogenesis of microbial endocarditis. Completion of these specific aims will permit investigators to better understand the interaction between the surface of NVS and cardiac valves. Finally, knowledge gained through these studies could lay the groundwork for a vaccine which would be beneficial to the population at high risk for this disease.

亚急性细菌性心内膜炎是一种严重的疾病，说明 所有住院和Viridans链球菌的0.3-3.0/1000 仍然是细菌心内膜炎的最常见原因。自1961年以来 认识到新的生物，营养变体 链球菌，大约在所有病例中造成5-10％ 链球菌心内膜炎。 NV是细菌的重要病原体 心内膜炎，因为患者出现较高程度的抗菌素 与其他形式的Viridans心内膜炎相比，失败，复发和死亡。 研究计划的总体目标是继续系统 研究营养变异链球菌的表面成分 （NVS）为了更好地了解这些细菌的相互作用 感染性亚急性细菌心内膜炎中的心脏瓣膜。 为了实现这一目标，我们计划：1。完成对的结构分析 缺陷链球菌和链球菌相邻组抗原。 2。确定负责链球菌粘附的身份 远离生物体对细胞外基质的依从性。分离和 通过标准纯化方案纯化粘附（单克隆 抗体和亲和色谱，疏水，离子交换，凝胶 渗透色谱法）和/或分子克隆（lambda gtll或 宇宙库）。 3。识别粘附上的结合域 （肽抑制研究和抗粘附的特异性去除 抗体）和相应的细胞外基质受体（S） 负责依从性链球菌菌株（光电反应性交叉 联系研究，单克隆抗体，免疫印迹）。 4。确定 粘附在防止缺陷性心内膜炎的保护中的作用。 大鼠心内膜炎模型将用于分析 启动心内膜炎的粘附。转座子灭活和\或 一亚硝酸缺失突变体也将与母体菌株进行比较 模型。最后，将确定抗粘附抗体的作用 防止NVS心内膜炎。 具体目的从结构和免疫化学分析开始 这些菌株的表面成分，并以研究 他们的结构功能关系在与和 心脏瓣膜定植，这是发病机理的主要步骤 微生物心内膜炎。这些特定目标的完成将允许 调查人员更好地了解表面之间的相互作用 NV和心脏瓣膜的。最后，通过这些知识获得了 研究可以为疫苗奠定基础，这将是有益的 对这种疾病的高风险人群。