Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.11889/4098
Title: Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis
Authors: Abdulrahman, Basant A.
Abu Khweek, Arwa
Akhter, Anwari
Caution, Kyle
Kotrange, Sheetal
Abdelaziz, Dalia H. A.
Newland, Christie
Rosales-Reyes, Roberto
Kopp, Benjamin
McCoy, Karen
Montione, Richard
Schlesinger, Larry S.
Gavrilin, Mikhail A.
Wewers, Mark D.
Valvano, Miguel A.
Amer, Amal O.
Keywords: Pneumonia - Prevention
Rapamycin - Pathophysiology
Cystic fibrosis - Pathophysiology
Phagocytosis
Issue Date: 1-Nov-2011
Citation: Basant A. Abdulrahman, Arwa Abu Khweek, Anwari Akhter, Kyle Caution, Sheetal Kotrange, Dalia H.A. Abdelaziz, Christie Newland, Roberto Rosales-Reyes, Benjamin Kopp, Karen McCoy, Richard Montione, Larry S. Schlesinger, Mikhail A. Gavrilin, Mark D. Wewers, Miguel A. Valvano & Amal O. Amer (2011) Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis, Autophagy, 7:11, 1359-1370, DOI: 10.4161/auto.7.11.17660
Abstract: Cystic fibrosis (CF) is the most common inherited lethal disease of Caucasians which results in multi organ dysfunction. However, 85% of the deaths are due to pulmonary infections. Infection by Burkholderia cenocepacia (B. cepacia) is a particularly lethal threat to CF patients because it causes severe and persistent lung inflammation and is resistant to nearly all available antibiotics. In CFTR ΔF508 mouse macrophages, B. cepacia persists in vacuoles that do not fuse with the lysosomes and mediates increased production of IL-1β. It is believed that intracellular bacterial survival contributes to the persistence of the bacterium. Here we show for the first time that in wild-type macrophages, many B. cepacia reside in autophagosomes that fuse with lysosomes at later stages of infection. Accordingly, association and intracellular survival of B. cepacia are higher in CFTR-ΔF508 (ΔF508) macrophages than in WT macrophages. An autophagosome is a compartment that engulfs non-functional organelles and parts of the cytoplasm then delivers them to the lysosome for degradation to produce nutrients during periods of starvation or stress. Furthermore, we show that B. cepacia down-regulates autophagy genes in WT and ΔF508 macrophages.However, downregualtion is more pronounced in ΔF508 macrophages since they already have compromised autophagy activity. We demonstrate that the autophagy-stimulating agent, Rapamycin markedly decreases B. cepacia infection in vitro by enhancing the clearance of B. cepacia via induced autophagy. In vivo, Rapamycin decreases bacterial burden in the lungs of CF mice and drastically reduces signs of lung inflammation. Together, our studies reveal that if efficiently activated, autophagy can control B. cepacia infection and ameliorate the associated inflammation. Therefore, autophagy is a novel target for new drug development for CF patients to control B. cepacia infection and accompanying inflammation.
Description: Authors include Basant A. Abdulrahman,Anwari Akhter, Kyle Caution, Sheetal Kotrange, Dalia H.A. Abdelaziz, Christie Newland, Roberto Rosales- Reyes, Benjamin Kopp, Karen McCoy, Richard Montione, Larry S. Schlesinger, Mikhail A. Gavrilin, Mark D. Wewers, Miguel A. Valvano & Amal O. Amer
URI: http://hdl.handle.net/20.500.11889/4098
Appears in Collections:Fulltext Publications



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