This research proposal is submitted to the Cystic Fibrosis Foundation Research Grant call to meet the timely priority of identifying new strategies to treat Methicillin Resistant S. aureus (MRSA) infections in cystic fibrosis (CF).
This is paramount since MRSA infections have increased dramatically in CF and are associated with non-resolving inflammation, a rapid decline in lung function, and shorter survival.
The ability of CF lungs to resolve inflammation and infections is defective and this defect can contribute to the pathogenesis of lung disease.
Evidence has emerged that endogenous pro-resolving mediators like resolvins (Rv) can be harnessed for reducing excessive inflammation, stimulating clearance of infections, and shortening the time to resolution. Administration of Rv in patients with CF could activate resolution of infection and inflammation as occurs in healthy individuals.
In a previous project funded by the CFF and in work in progress we have learned that RvD1 reduces chronic P. aeruginosa burden, inflammation, and organ damage in CF mice and human cells. Therefore, it is imperative to delineate actions and therapeutic potential of resolvins on MRSA infection.
To address this paramount and timely goal, we assembled a multipronged project with 2 aims:
1. Determining if resolvins stimulate clearance of MRSA in CF
2. Assessing if resolvins promote resolution of inflammation due to MRSA
In Aim 1, actions and efficacy of RvD1 and D2 in reducing lung MRSA burden and enhancing clearance mechanisms will be assessed in CF mice and human cells. This will be the foundation for evaluating, in Aim 2, if RvD1 and D2 curb excessive airway inflammation and damage that contribute to the progressive lung disease in CF.
Completion of these aims will define broad actions of resolvins that can be harnessed for treating persistent MRSA infections, which is a contributor of morbidity and mortality of CF