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.

项目总结