Prevention and therapy of Staphylococcus aureus infections

金黄色葡萄球菌感染的预防和治疗

• 批准号: 8046919
• 负责人: Olaf Schneewind
• 金额: $ 233.51万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046919
• 关键词: Address; Adenosine; Agglutination; Agglutinins; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibodies; Antigen Presentation; Antigens; Apoptotic; Attenuated; B-Lymphocytes; Basic Science; Binding Proteins; Blocking Antibodies; Blood Circulation; Blood Clot; Blood coagulation; Cleaved cell; Coagulase; Coagulation Process; Communicable Diseases; Community Hospitals; Complement; Deposition; Disease; Failure; Fibrin; Fibrinogen; Generations; Genomics; Genotype; Genus staphylococcus; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunosuppression; Infection; Investments; Kinetics; Knowledge; Lead; Lesion; Libraries; Lower respiratory tract structure; Mediating; Membrane Proteins; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Nosocomial Infections; Pathogenesis; Phagocytosis; Phase; Prevention; Prevention therapy; Property; Proteins; Prothrombin; Reporting; Research; Resources; Scientist; Screening procedure; Skin; Soft Tissue Infections; Staphylococcal Infections; Staphylococcal Protein A; Staphylococcal Vaccines; Staphylococcus aureus; Superantigens; Surface; Technology; Therapeutic; Time; Tissues; Translating; United States National Institutes of Health; Vaccination; Vaccines; Variant; Virulence; design; global health; high throughput technology; human disease; human monoclonal antibodies; human mortality; human subject; improved; in vitro Assay; macrophage; methicillin resistant Staphylococcus aureus; mortality; mutant; neutralizing antibody; neutrophil; new technology; novel; pathogen; prevent; programs; protein expression; public health relevance; quantum; resistant strain; response; tool; vaccine development; von Willebrand Factor

DESCRIPTION (provided by applicant): This proposal addresses Theme 4 (Focusing on global health) of NIH RFA-OD-10-005 by aiming to generate staphylococcal vaccines. The project also addresses Theme 1 (Applying Genomics and Other High Throughput Technologies) through the systematic analysis of human B cell responses as well as Theme 2 (Translating Basic Science Discoveries into New and Better Treatments) through the invention of a novel treatment - therapeutic vaccination - for human MRSA infections. Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the world. Antibiotic resistant strains (MRSA) are isolated in more than half of all community and hospital infections, and humans that survive MRSA infections do not develop protective immunity. We report that MRSA evasion from host protective immune responses is triggered by two surface molecules, adenosine synthase A (AdsA) and protein A (SpA). AdsA produces the immune suppressive molecule adenosine, whereas SpA triggers the apoptotic collapse of B cell immune responses. Studies on host immune responses to challenge with attenuated S. aureus strains and on the immunity elicited from purified staphylococcal subunit antigens lead us to propose that protective immunity against MRSA is achieved via neutralizing antibodies, which block the pathogen's coagulation and agglutination strategies during infection. Enabled by the availability of an exciting new technology - high-throughput isolation of monoclonal antibodies from human plasmoblasts - we propose here the systematic analyses of B cell responses for neutralizing antibodies against staphylococcal AdsA, SpA, coagulases and agglutinins. These antibodies will be used to define the hitherto elusive attribute of protective immunity against MRSA infections using in vitro assays and animal models for staphylococcal diseases. Once endowed with such information, we will generate immune therapeutics for the treatment of MRSA infections and vaccines to globally prevent staphylococcal infections. This ARRA proposal represents a one-time investment into a unique knowledge gap and a technological opportunity with a probable quantum yield of returns in translational products. Beyond its initial phase of discovery, this research program is designed to attract private resources leading to the development of vaccines that can protect humans from disease and thereby improve Global Health. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus, in particular antibiotic resistant isolates (MRSA), are a leading cause of infectious disease morbidity and mortality in the world. However, vaccines or immune therapeutics against MRSA are not available. During staphylococcal infection, protein A, coagulase and von-Willebrand-Factor binding-protein impart toxic functions on blood clotting or immune suppression that can be overcome through the generation of specific immune responses directed against these factors. These technologies will be developed with the goal of generating a vaccine and immune therapeutics, thereby providing protection against S. aureus infections and improving global health.

描述（由申请人提供）：该提案通过旨在生成葡萄球菌疫苗来解决NIH RFA-OD-10-005的主题4（侧重于全球健康）。该项目还通过系统地分析人类B细胞反应以及主题2（将基础科学发现转化为新的，更好的治疗方法）通过发明新型治疗方法 - 治疗治疗疫苗 - 用于人类MRSA感染。 金黄色葡萄球菌是世界上血流，下呼吸道，皮肤和软组织感染的主要原因。在所有社区和医院感染的一半以上，抗生素耐药菌菌株（MRSA）分离出来，而生存MRSA感染的人类不会发展保护性免疫。我们报告说，从宿主保护性免疫反应中逃避MRSA是由两个表面分子，腺苷合酶A（ADSA）和蛋白A（SPA）触发的。 ADSA产生免疫抑制性分子腺苷，而水疗中心会触发B细胞免疫反应的凋亡塌陷。对宿主免疫反应的研究对减弱的金黄色葡萄球菌菌株的挑战以及纯化的葡萄球菌亚基抗原引起的免疫力使我们提出，通过中和抗体可以通过中和抗体来实现对MRSA的保护性免疫，从而阻止病原体的凝结和凝集策略在感染过程中。通过一种令人兴奋的新技术的可用性 - 从人纤溶酶细胞中的单克隆抗体进行了高通量隔离 - 我们在这里提出了对中和抗葡萄球菌ADSA，SPA，SPA，SPA，辅助酶和凝集素的B细胞反应的系统分析。这些抗体将用于定义迄今为止使用体外测定法和动物模型用于葡萄球菌疾病的迄今为止难以抗衡的免疫属性。一旦获得此类信息，我们将生成免疫疗法，用于治疗MRSA感染和疫苗以预防葡萄球菌感染。该ARRA建议代表了对独特的知识差距和技术机会的一次性投资，具有转化产品中可能收益量的量子收益率。除了最初的发现阶段，该研究计划旨在吸引私人资源，从而开发可以保护人类免受疾病并从而改善全球健康的疫苗。 公共卫生相关性：金黄色葡萄球菌，尤其是抗生素抗性分离株（MRSA），是世界上传染病发病率和死亡率的主要原因。但是，尚无针对MRSA的疫苗或免疫治疗剂。在葡萄球菌感染期间，蛋白A，凝结酶和Von-Willebrand因素结合蛋白会赋予血液凝结或免疫抑制的毒性功能，这些功能可以通过针对这些因素的特定免疫反应来克服。这些技术将开发，目的是产生疫苗和免疫治疗剂，从而为金黄色葡萄球菌感染提供保护并改善全球健康状况。