Association of Staphylococcus aureus infection with autoimmunity in cystic fibrosis

项目摘要 该建议的目的是建立S.金黄色葡萄球菌呼吸道感染 和自身免疫性囊性纤维化（CF）。CF是一种致命的遗传性疾病，影响全球70，000人。 在CF中，肺损伤是大多数疾病发病率和死亡率的原因。虽然CF肺宿主 多种微生物感染，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。S.金黄色葡萄球菌感染最近急剧上升， 耐甲氧西林菌株在CF中构成巨大威胁。虽然高达60%的CF患者可以感染 S.金黄色葡萄球菌，它仍然在很大程度上是未知的宿主因素有利于S。金黄色葡萄球菌感染。自身免疫可能 提供了一个新的，意想不到的解释，为什么CF患者感染了S。金黄色。虽然CF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被低估。我们的初步结果表明 高水平的某些自身抗体显示出与S.金黄色葡萄球菌感染 在有限的成人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病发病机制中的作用。该提案的目的是建立一个关联之间的S。金黄色 感染和保护性非致病性自身抗体。核心假设是， 非致病性、有益的自身抗体与缺乏S.金黄色葡萄球菌感染在一个大的，成人和 儿科、CF队列，并增强免疫系统清除S.金黄色。来测试我们 假设，在我们的具体目标，我们将确定之间的关联S。金黄色葡萄球菌肺部感染和 这些非致病性自身抗体的水平在一个大的，统计学上可靠的CF患者队列。我们将 并探讨这些自身抗体改善S.金黄色葡萄球菌清除率 在CF航空公司。仅人细胞、CF临床分离的S.金黄色葡萄球菌和CF生物标本用于此 致力于增强该项目的人类医学相关性。我们提出的工作有可能 实现以下预期结果：1）鉴定保护CF患者的新宿主因子 对于S.金黄色葡萄球菌肺部感染; 2）加深对金黄色葡萄球菌的认识;金黄色葡萄球菌在CF发病机制，3）揭示了一个 免疫系统能够对抗S.金黄色葡萄球菌，包括耐甲氧西林 S.金黄色葡萄球菌菌株，以及4）提出任何自身抗体在CF气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 免疫系统对抗S.金黄色葡萄球菌在CF气道，将使设计新的，未来，免疫调节 干扰S. CF中的金黄色葡萄球菌感染总的来说，目前的建议将具有积极的意义。 通过探索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.