Association of Staphylococcus aureus infection with autoimmunity in cystic fibrosis

金黄色葡萄球菌感染与囊性纤维化自身免疫的关系

• 批准号: 10353431
• 负责人: Balazs Rada
• 金额: $ 19.08万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-16 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353431
• 关键词: Adult; Affect; Airway Disease; Antigen Targeting; Apoptosis; Apoptotic; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Bacteria; Biological; Biological Assay; Cells; Clinical; Cystic Fibrosis; Cytolysis; Data; Disease; Enzyme-Linked Immunosorbent Assay; Future; Genetic Diseases; Goals; Health; Human; Immune system; Immunoglobulin M; In Vitro; Infection; Integration Host Factors; Knowledge; Link; Lung infections; Measures; Mediating; Medical; Methicillin Resistance; Mission; Morbidity - disease rate; Necrosis; Outcome; Outcome Measure; Pathogenesis; Persons; Play; Proliferating Cell Nuclear Antigen; Proteins; Public Health; Pulmonary Cystic Fibrosis; Research; Respiratory Tract Infections; Role; Serum; Solid; Staphylococcus aureus; Staphylococcus aureus infection; Testing; United States National Institutes of Health; Work; airway inflammation; children with cystic fibrosis; clinically significant; cohort; cystic fibrosis airway; cystic fibrosis infection; cystic fibrosis patients; design; fighting; human disease; immunoregulation; improved; in vitro Assay; lung health; lung injury; macrophage; methicillin resistant Staphylococcus aureus; mortality; neutrophil; novel; pathogenic bacteria; pulmonary function; recruit; resistant strain; single molecule; systemic autoimmunity

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.

项目摘要 该提案的目的是建立金黄色葡萄球菌呼吸道感染之间的临床关联 和囊性纤维化（CF）的自身免疫性。 CF是一种致命的遗传疾病，全球影响70,000人。 在CF中，肺部损害是疾病发病率和死亡率的大多数。而CF肺主持人 多数菌感染，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。金黄色葡萄球菌感染最近显着上升并出现 耐甲氧西林的菌株在CF中构成了巨大威胁。虽然可以感染多达60％的CF患者 金黄色葡萄球菌，在很大程度上尚不清楚哪种宿主因素有利于金黄色葡萄球菌感染。自身免疫可以 提供了一种新颖的，出乎意料的解释，为什么CF患者感染了金黄色葡萄球菌。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以升高 在CF中表明该疾病的自身免疫成分不足。我们的初步结果显示 高水平的某些自身抗体表现出与金黄色葡萄球菌感染的显着关联 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疾病发病机理中。该提议的目的是建立金黄色葡萄球菌之间的关联 CF中的感染和保护性非致病性自身抗体。中心假设是特定的， 非致病性，有益的自身抗体与大型成人和成人缺乏金黄色葡萄球菌感染相关 小儿，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，在我们的具体目的中，我们将确定金黄色葡萄球菌感染与 这些非对照自身抗体的水平在大型统计稳固的CF患者中。我们将 还探索这些自身抗体可以改善金黄色葡萄球菌间隙的潜在机制 在CF气道中。在此中，只有人类细胞，金黄色葡萄球菌和CF生物测试的CF临床分离株才能使用 增强该项目的人类医学相关性的工作。我们提出的工作有可能 达到以下预期结果：1）鉴定保护CF患者的新型宿主因子 反对金黄色葡萄球菌感染，2）对CF中金黄色葡萄球菌的发病机理的更深入了解，3）揭示 免疫系统能够与金黄色葡萄球菌作斗争的新机制，包括耐甲氧西林 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。这项工作的理由是确定特定的自动抗体是否有助于 在CF Airways中与金黄色葡萄球菌作斗争的免疫系统将使您能够设计新颖，未来，免疫调节 干扰Cf中的金黄色葡萄球菌感染的方法。总体而言，当前的提议将有积极的 通过探索S. 金黄色葡萄球菌呼吸道感染和特定自身抗体。