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.
The proposed research is relevant to public health because establishing a clinical link between S. aureus respiratory infection and specific autoantibodies in cystic fibrosis is expected to advance our understanding of cystic fibrosis airway inflammation, autoimmunity and reveal novel options to eradicate S. aureus from CF airways. Thus, the proposed research is important to the mission of the NIH by developing fundamental knowledge that will help to fight human diseases.
