Autophagy Stimulation Manipulates Burkholderia cenocepacia Infection in a Cystic Fibrosis Mouse Model

Cystic fibrosis (CF) is the most common inherited lethal disease of Caucasians. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator which results in multi organ dysfunction. The most common mutation is the ΔF508. Infection by Burkholderia cenocepacia (BC) is a particularly lethal threat to CF patients because it causes severe and persistent lung inflammation. Autophagy is a cell survival mechanism in which, an autophagosome, engulfs non‐functional organelles then delivers them to the lysosome for degradation. Our Immunofluorescence (IF) data demonstrated that autophagy is defective in ΔF508 macrophages. The ubiquitin binding adaptor protein p62 is needed to deliver several types of ubiquitinated cargoes to the autophagosomes. Our IF and Colony Forming Unite assay in wild type (WT) macrophages showed that when P62 is down regulated using siRNA, the bacterial survival increased. Interestingly, when we over expressed p62, we observed a significant decrease in the bacterial survival. The ΔF508 macrophages did not respond similarly to WT showing a problem in the delivery of BC to the autophagosomes. Here, we demonstrate that an autophagy inducer, Rapamycin, markedly decreases BC infection by enhancing the clearance of BC. Therefore, this study reveals that autophagy is a novel target for new drug development for CF patients to control BC infection and accompanying inflammation.