REGULATION OF INFLAMMATION, LUNG INJURY AND AUTOPHAGY DURING PSEUDOMONAS AERUGINOSA LUNG INFECTION

Abstract

Pseudomonas aeruginosa is an opportunistic bacterial pathogen which causes acute and chronic infections in immune compromised individuals, including cystic fibrosis (CF) patients where it represents the leading cause of morbidity and mortality. Early inflammatory responses are sufficient to clear P. aeruginosa infections in healthy individuals. However dysregulation of these responses in many disease states greatly increases susceptibility to infection with the bacteria. Herein we identify regulator of calcineurin-1 and calcineurin Aβ as novel negative and positive regulators of P. aeruginosa induced inflammation respectively. Furthermore these studies reveal substantial cross talk between pathways leading to activation of the inflammatory transcription factors NFAT and NFκB which creates biologically significant signaling redundancy following P. aeruginosa lung infection. Other components of innate immunity against P. aeruginosa are also explored; including a novel role for the evolutionarily conserved catabolic process autophagy during bacterial clearance. Combined with the recent landmark findings that autophagy is impaired in the lungs of CF patients, these findings highlight an emerging potential for ‘autophagy restorative therapy’ in the treatment of CF associated lung infections. Finally, a protective role for mast cells during P. aeruginosa induced acute lung injury is revealed. Together these findings greatly enhance our understanding of mechanisms of host defense during early innate immune responses against P. aeruginosa bacteria, and reveal novel opportunities for therapeutic intervention which could significantly decrease P. aeruginosa associated morbidity and mortality.