Association of Staphylococcus aureus infection with autoimmunity in cystic fibrosis

项目总结 这项建议的目的是建立金黄色葡萄球菌呼吸道感染之间的临床联系。 囊性纤维化(CF)的自身免疫。慢性萎缩性胃炎是一种致命的遗传病，影响着全球7万人。 在慢性阻塞性肺疾病中，肺损伤是导致大多数疾病发病率和死亡率的原因。而CF肺则是 多菌感染，只有少数细菌病原体与肺功能下降有关 包括金黄色葡萄球菌。美国金黄色葡萄球菌感染最近急剧上升，并出现了 耐甲氧西林菌株对慢性萎缩性胃炎构成极大威胁。而多达60%的慢性萎缩性胃炎患者可能感染 关于金黄色葡萄球菌，目前尚不清楚哪些宿主因素有利于金黄色葡萄球菌的感染。自身免疫力可能 提供了一个新的、意想不到的解释，为什么CF患者会感染金黄色葡萄球菌。而CF则不是 被认为是一种自身免疫性疾病，我们和其他人已经确定了几种自身抗体升高 在CF中，表明疾病的自身免疫成分未得到充分认识。我们的初步结果显示 某些自身抗体的高水平与金黄色葡萄球菌感染的存在显著相关 在一个有限的成人CF队列的血清中。我们的长期研究目标是确定自身免疫的作用 在CF病的发病机制中。这项建议的目的是在金黄色葡萄球菌之间建立联系 CF中的感染和保护性、非致病性自身抗体。中心假设是，具体的， 非致病性、有益的自身抗体与缺乏金黄色葡萄球菌感染有关，在大型、成人和 儿科，CF队列，并增强免疫系统清除金黄色葡萄球菌的能力。测试我们的 假设，在我们的特定目标中，我们将确定金黄色葡萄球菌肺部感染与 这些非致病性自身抗体的水平在一大批统计可靠的CF患者队列中。我们会 也探讨了这些自身抗体促进金黄色葡萄球菌清除的潜在机制(S) 在CF航空公司。只有人类细胞、金黄色葡萄球菌的CF临床分离株和CF生物检疫菌种被用于这项研究 加强该项目的人类医学相关性的工作。我们提议的工作有可能 实现以下预期结果：1)确定保护CF患者的新宿主因子 抗金黄色葡萄球菌肺部感染，2)加深对金黄色葡萄球菌致病机制的理解，3)揭示 免疫系统能够对抗包括耐甲氧西林在内的金黄色葡萄球菌的新机制 金黄色葡萄球菌菌株，以及4)提出了任何自身抗体在CF呼吸道疾病中的第一个有益作用 发病机制。这项工作的基本原理是，确定特定的自身抗体是否有助于 免疫系统在CF呼吸道对抗金黄色葡萄球菌，将使新型、未来、免疫调节剂的设计成为可能 干预金黄色葡萄球菌感染的途径。总体而言，目前的提议将产生积极的影响 通过探索令人兴奋的S。 金黄色葡萄球菌呼吸道感染和特异性自身抗体。

Project summary The aim of this proposal is to establish a clinical association between S. aureus respiratory infection and autoimmunity in cystic fibrosis (CF). CF is a fatal genetic disease affecting 70,000 people worldwide. In CF, lung damage is responsible for the majority of disease morbidity and mortality. While CF lungs host polymicrobial infections, only a few bacterial pathogens have been linked to decline in lung function including Staphylococcus aureus. S. aureus infections have recently risen dramatically and emerged methicillin-resistant strains pose a great threat in CF. While up to 60% of CF patients can be infected with S. aureus, it remains largely unknown what host factors favor S. aureus infection. Autoimmunity could provide a novel, unexpected explanation why CF patients get infected with S. aureus. While CF is not considered an autoimmune disease, we and others have identified several autoantibodies to be elevated in CF indicating an underappreciated autoimmune component of the disease. Our preliminary results show that high levels of certain autoantibodies show striking association with the absence of S. aureus infection in sera of a limited adult CF cohort. Our long-term research goal is to determine the role of autoimmunity in CF disease pathogenesis. The objective of this proposal is to establish an association between S. aureus infection and protective, nonpathogenic autoantibodies in CF. The central hypothesis is that specific, nonpathogenic, beneficial autoantibodies correlate with lack of S. aureus infection in a large, adult and pediatric, CF cohort, and enhance the ability of the immune system to clear S. aureus. To test our hypothesis, in our specific aims we will determine association between S. aureus lung infection and the levels of these nonpathogenic autoantibodies in a large, statistically solid cohort of CF patients. We will also explore the potential mechanism(s) by which these autoantibodies could improve S. aureus clearance in the CF airways. Only human cells, CF clinical isolates of S. aureus and CF biospecimen are used in this work enhancing the human medical relevance of this project. Our proposed work has the potential to achieve the following expected outcomes: 1) identification of a novel host factor that protects CF patients against S. aureus lung infection, 2) deeper understanding of S. aureus pathogenesis in CF, 3) revealing a new mechanism by which the immune system is capable of fighting S. aureus including methicillin-resistant S. aureus strains, and 4) proposing the first beneficial role of any autoantibody in CF airway disease pathogenesis. The rationale of this work is that determining whether specific autoantibodies help the immune system to fight S. aureus in CF airways, will enable the design of novel, future, immunomodulatory approaches to interfere with S. aureus infection in CF. Overall, the current proposal will have a positive impact in the fields of CF airway infections and autoimmunity by exploring an exciting new link between S. aureus respiratory infections and specific autoantibodies.