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.