Pathobiology of Staphyloccocus areus Endocarditis

沙葡萄球菌心内膜炎的病理学

• 批准号: 8316121
• 负责人: Peter Rolf Panizzi
• 金额: $ 24.35万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-10 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316121
• 关键词: Accounting; Active Sites; Acute; Adult; Age; Antibiotic Resistance; Antibiotic Therapy; Argatroban; Bacterial Endocarditis; Bacterial Infections; Biochemical; Clinical; Coagulase; Complex; Development; Diagnosis; Disease; Drug Kinetics; Endocarditis; Factor XIII; Fibrin; Fibrin fragment D; Fibrinogen; Fluorescence; Generations; Goals; Heart Valves; Image; Imaging Techniques; Immunology; Incidence; Infection; Label; Mediating; Molecular; Neonatal; Pathology; Phase; Play; Positron-Emission Tomography; Prothrombin; Research; Role; Specificity; Staphylocoagulase; Staphylococcus aureus; Testing; Transesophageal Echocardiography; Validation; Virulence Factors; X-Ray Computed Tomography; analog; crosslink; design; improved; in vivo; inhibitor/antagonist; insight; molecular imaging; mortality; mouse model; novel; prothrombin activator; tomography

The broad goal ofthis proposed research is to determine the underlying molecular mechanisms required for S. aureus endocarditis vegetations to develop and to improve diagnosis of endocarditis by the use of state-of-the-art molecular imaging techniques. Acute bacterial endocarditis (ABE) is a potentially deadly disease caused by bacterial infection of heart valves. Coagulase-positive S. aureus infections are the leading cause of ABE and have the highest mortality rates, due to the increased incidence of antibiotic-resistance. 5. aureus expresses a unique non-proteolytic prothrombin (ProT) activator, staphylocoagulase that mediates recognition of fibrinogen by the active staphylocoagulase-ProT complex resulting in conversion of fibrinogen to fibrin. Fibrin generation is hypothesized to play a critical role in ABE pathology. During the K99 phase of my project, we developed novel active site-labeled ProT analogs that were use in Fluorescence Molecular Tomography (FMT) and Positron Emission Tomography fused with Computed Tomography (PETCT) studies to identify 5. aureus ABE, non-invasively in a mouse model ofthe disease. We discovered that staphylocoagulase not only activates ProT, but also localizes the staphylocoagulase- ProT complex to S. aureus vegetations by COOH-terminal interactions with Fragment D of fibrin/fibrinogen. Here, my newly established lab will use these imaging agents to assess whether staphylocoagualse is a virulence factor for 5. aureus in endocarditis. Furthermore, specific recognition of vegetations by our new endocarditis probes would aid in determining the role and importance of factor Xllla cross-linking to the pathology of endocarditis and facihtate identification of new adjunctive therapies targeting fibrin generation. Molecular imaging, biochemical, and immunology studies are proposed to test our hypotheses: that these SC is a virulence factor; that factor XIII activation stabilizes the fibrin network during ABE; and that new adjunctive therapies can limit vegetation grow in ABE. Specific Aims are: (1) To determine whether staphylocoagulase is a virulence factor for S. aureus endocarditis (2) To determine whether S. aureus-induces activation of FXIII and fibrin cross-linking during ABE; and (3) To characterize the effect of argatroban and staphylocoagulase inhibitors on the vegetation development during ABE.

这项研究的总体目标是确定潜在的分子机制 金黄色葡萄球菌心内膜炎赘生物形成和改善心内膜炎诊断所需 通过使用最先进的分子成像技术。急性细菌性心内膜炎（ABE）是一种 由心脏瓣膜细菌感染引起的潜在致命疾病。凝固酶阳性金黄色葡萄球菌 感染是 ABE 的主要原因，并且死亡率最高，因为 抗生素耐药性的发生率。 5.金黄色葡萄球菌表达独特的非蛋白水解凝血酶原 (ProT) 激活剂，葡萄球菌凝固酶，介导活性物质对纤维蛋白原的识别 葡萄球菌凝固酶-ProT 复合物导致纤维蛋白原转化为纤维蛋白。纤维蛋白的生成是 假设在 ABE 病理学中发挥关键作用。在我的项目的 K99 阶段，我们 开发了新型活性位点标记的 ProT 类似物，用于荧光分子 断层扫描 (FMT) 和正电子发射断层扫描与计算机断层扫描 (PETCT) 融合 研究在小鼠模型中以非侵入方式识别 5. 金黄色葡萄球菌 ABE。我们 发现葡萄球菌凝固酶不仅激活ProT，而且还定位葡萄球菌凝固酶- 通过 COOH 末端与片段 D 相互作用形成金黄色葡萄球菌植被的 ProT 复合物 纤维蛋白/纤维蛋白原。在这里，我新建立的实验室将使用这些显像剂来评估是否 葡萄球菌凝固酶是心内膜炎中金黄色葡萄球菌的毒力因子。此外，具体 通过我们的新心内膜炎探针识别赘生物将有助于确定其作用和 XIIIa 因子交联对心内膜炎病理学的重要性并有助于识别 针对纤维蛋白生成的新辅助疗法。分子成像、生物化学和 建议进行免疫学研究来检验我们的假设：这些 SC 是毒力因子；那 XIII 因子激活可在 ABE 期间稳定纤维蛋白网络；以及新的辅助疗法 会限制 ABE 中的植被生长。具体目标是： (1) 确定是否 葡萄球菌凝固酶是金黄色葡萄球菌心内膜炎的毒力因子 (2) 确定葡萄球菌是否是金黄色葡萄球菌心内膜炎的毒力因子。 金黄色葡萄球菌 - 在 ABE 过程中诱导 FXIII 和纤维蛋白交联的激活； (3) 表征 阿加曲班和葡萄球菌凝固酶抑制剂对 ABE 期间植被发育的影响。