Prevention and therapy of Staphylococcus aureus infections

描述(由申请人提供)：该提案针对NIH RFA-OD-10-005的主题4(关注全球健康)，旨在生产葡萄球菌疫苗。该项目还涉及主题1(应用基因组学和其他高通量技术)，通过系统分析人类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)，通过发明治疗人类耐甲氧西林金黄色葡萄球菌感染的新疗法--治疗性疫苗。金黄色葡萄球菌是世界上引起血液、下呼吸道、皮肤和软组织感染的主要原因。抗生素耐药菌株(MRSA)在超过一半的社区和医院感染中被分离出来，在MRSA感染中幸存下来的人类不会产生保护性免疫。我们报道了MRSA逃避宿主保护性免疫反应是由两个表面分子，腺苷合成酶A(ADSA)和蛋白A(SpA)触发的。ADSA产生免疫抑制分子腺苷，而SpA则触发B细胞免疫反应的凋亡性崩溃。通过研究宿主对金黄色葡萄球菌减毒株攻击的免疫反应，以及从纯化的葡萄球菌亚单位抗原诱导的免疫反应，我们提出对MRSA的保护性免疫是通过中和抗体来实现的，中和抗体在感染过程中阻断病原体的凝血和凝集策略。在一项激动人心的新技术--从人浆母细胞中高通量分离单抗--的支持下，我们在这里提出了对B细胞中和抗葡萄球菌ADSA、SpA、凝固酶和凝集素抗体的系统分析。这些抗体将用于通过葡萄球菌疾病的体外分析和动物模型来确定迄今难以捉摸的针对MRSA感染的保护性免疫属性。一旦获得这些信息，我们将产生治疗MRSA感染的免疫疗法和全球预防葡萄球菌感染的疫苗。ARRA的这项提议代表了对独特的知识鸿沟的一次性投资和翻译产品可能获得量子回报的技术机会。除了最初的发现阶段，这项研究计划旨在吸引私人资源，从而开发能够保护人类免受疾病侵袭的疫苗，从而改善全球健康。 公共卫生相关性：金黄色葡萄球菌，特别是耐药菌株(MRSA)，是世界上传染病发病率和死亡率的主要原因。然而，目前还没有针对MRSA的疫苗或免疫疗法。在葡萄球菌感染过程中，蛋白A、凝固酶和von-Willebrand因子结合蛋白对凝血或免疫抑制具有毒性作用，可通过产生针对这些因子的特异性免疫反应来克服。开发这些技术的目标是开发疫苗和免疫疗法，从而提供对金黄色葡萄球菌感染的保护，并改善全球健康。

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.