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A3866 - Cystic Fibrosis Variants of P. Aeruginosa Attenuate Host PPARgamma Expression in Epithelial Cells and Macrophages
Author Block: B. Bedi1, N. M. Maurice2, K. M. Bijli2, Z. Yuan3, J. J. Varga4, J. Wenjing4, J. B. Goldberg4, A. A. Stecenko5, C. Hart1, R. T. Sadikot1; 1Pulmonary, Allergy, Critical care and Sleep Medicine, Atlanta VA Med Ctr/Emory Univ, Decatur, GA, United States, 2Medicine, Emory University, Atlanta, GA, United States, 3Medicine, Emory University, Decatur, GA, United States, 4Peditrics, Cystic fibrosis, Emory University, Atlanta, GA, United States, 5Peditrics, Cystic fibrosis, Emory Univ Sch of Med, Atlanta, GA, United States.
Chronic pulmonary infections continue to be the predominant cause of morbidity in patients with cystic fibrosis (CF). Emerging multidrug resistant as well as genotypical alterations of P. aeruginosa strains in CF are an increasing threat in these patients. Hence there is an urgent need to develop new strategies to combat P. aeruginosa infections. In CF the initial colonization with non-mucoid P. aeruginosa strains is often followed by the predominance of the mucoid form in the subsequent course of the disease, which is related to a poor prognosis. It is imperative to study the modulation of host defense mechanisms by non-mucoid and mucoid CF strains. Strategies that strengthen the ability of the host to inhibit virulence factors would allow for enhanced bacterial clearance and could be employed in the treatment of resistant infections. Recently we have shown that the laboratory strain of P. aeruginosa (PAO1) inhibits expression of Peroxisome proliferator-activated receptor gamma (PPARγ) in macrophages. Here we investigated the effects CF isolates of P. aeruginosa (mucoid and non-mucoid) on PPARγ and its dependent genes in macrophages and epithelial cells. Human moncocyte derived macrophages and epithelial cells treated with CFBR 573 and 450 (non-mucoid), CFBR 388 and 309 (mucoid) P. aeruginosa (MOI of 1) showed significantly reduced expression of PPARγ message and protein in a time dependent manner. Furthermore PPARγ-dependent genes, CD36 (a scavenger receptor) and Paraoxanase-2 (PON-2) an enzyme that possesses lactonase activity, which enhances the hydrolysis of quorum sensing molecules, were also inhibited by these isolates. Pioglitazone (10 μM) a PPARγ ligand enhanced the clearance of P. aeruginosa from macrophages infected with P. aeruginosa. Mechanistically we show that PPARγ agonists mediate clearance of non-mucoid and mucoid strains by enhancing PON-2 expression in macrophages. We also demonstrate the impact of non-mucoid and mucoid strains on epithelial cell barrier function. Additionally, we show that the bacterial virulence can exacerbate the impact of dysfunctional Cystic fibrosis transmembrane conductance regulator (CFTR) on cellular metabolism. Together these data show that CF both non-mucoid and mucoid isolates of P. aeruginosa inhibit expression of PPARγ in host cells and compromise cellular function, suggesting a mechanism by which bacteria evade host defenses. Our studies suggest a role for PPARγ immunotherapy for P. aeruginosa infections in patients with CF.