Project summary description
In cystic fibrosis (CF), lung damage is responsible for the majority of disease morbidity and
mortality. While CF lungs host polymicrobial infections, lung disease has only been linked to a few
bacterial pathogens including Staphylococcus aureus. S. aureus is the most prevalent infectious agent
in the respiratory tract of CF patients. Neutrophil granulocytes represent the most powerful component
of the healthy immune system to kill S. aureus. In CF, though, neutrophils fail to eliminate this bacterium
despite their robust recruitment to the airways. It remains largely unknown why neutrophils in CF cannot
eliminate S. aureus. Our published results show that the CF airway environment reduces the ability of
human neutrophils to kill CF isolates of S. aureus. In contrast, the CF sputum does not affect S. aureus
phagocytosis by neutrophils, extrusion of neutrophil extracellular traps or neutrophil viability. Our
additional data demonstrate that CF blood neutrophils are not impaired in their abilities to kill S. aureus
in vitro but the CF sputum also reduces their bactericidal activities against this bacterium. Our long-term
goal is to identify why CF patients are unable to clear S. aureus from their airways. Our goal in this
proposal is to determine which components of the CF sputum are responsible for its inhibitory action on
neutrophils’ S. aureus killing. The rationale of the proposed work is that a deeper understanding of S.
aureus pathogenesis in CF will aid to develop new, anti-staphylococcal intervention strategies for CF in
the near future. Our central hypothesis is that a concerted action of IgG immune complexes and
exosomes present in the CF sputum mediate the inhibitory action of CF sputum on S. aureus killing by
neutrophils. Our proposed work will be expected to determine the exact component(s) of the CF sputum
that compromise(s) the ability of neutrophils to kill S. aureus. This knowledge is essential for our better
understanding of airway inflammation, host-pathogen interactions and S. aureus pathogenesis in CF. In
addition, this exploratory work will open future studies focusing on the exact mechanism of how the CF
sputum components identified here impair neutrophil functions and on exploring new, neutrophil-targeting
therapies for CF.