title: Pseudomonas toxin pyocyanin triggers autophagy: Implications for pathoadaptive mutations.
abstract: Pseudomonas aeruginosa can establish life-long chronic infection in patients with cystic fibrosis by generating genetic loss-of-function mutations, which enhance fitness of the bacterium in the airways. However, the precise role of the pathoadaptive mutations in persistence in chronic airways infection remains largely unknown. Here we demonstrate that pyocyanin, a well-described P. aeruginosa virulence factor that plays an important role in the initial infection, promotes autophagy in bronchial epithelial cells. Disruption of phzM, which is required for pyocyanin biosynthesis, leads to a significant reduction in autophagy in Beas-2B cells and lung tissues. Pyocyanin-induced autophagy is mediated by the EIF2AK4/GCN2-EIF2S1/eIF2α-ATF4 pathway. Interestingly, rats infected with the phzMΔ mutant strain have high mortality rate and numbers of colony-forming units, compared to those infected with wild-type (WT) P. aeruginosa PA14 strain, during chronic P. aeruginosa infection. In addition, the phzMΔ mutant strain induces more extensive alveolar wall thickening than the WT strain in the pulmonary airways of rats. As autophagy plays an essential role in suppressing bacterial burden, our findings provide a detailed understanding of why reduction of pyocyanin production in P. aeruginosa in chronic airways infections has been associated with better host adaptation and worse outcomes in cystic fibrosis.
authors.affiliation: a Key State Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University , Kunming , Yunnan , China.|b Faculty of Basic Medicine, Yunnan University of Traditional Chinese Medicine , Kunming , Yunnan , China.
authors.forename: Zhong-Shan
authors.initials: ZS
authors.lastname: Yang
authors.affiliation: c Yunnan Institute of Digestive Disease, Department of Digestive Diseases, The First Affiliated Hospital, Kunming Medical University , Kunming , Yunnan , China.
authors.forename: Lan-Qing
authors.initials: LQ
authors.lastname: Ma
authors.affiliation: d Institute of Microbiology, Chinese Academy of Science , Beijing , China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhu
authors.affiliation: a Key State Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University , Kunming , Yunnan , China.
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Yan
authors.affiliation: e Department of Pathology , The First Affiliated Hospital, Kunming Medical University , Kunming , Yunnan , China.
authors.forename: Li
authors.initials: L
authors.lastname: Bian
authors.affiliation: a Key State Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University , Kunming , Yunnan , China.
authors.forename: Ke-Qin
authors.initials: KQ
authors.lastname: Zhang
authors.affiliation: a Key State Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University , Kunming , Yunnan , China.
authors.forename: Cheng-Gang
authors.initials: CG
authors.lastname: Zou
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001427:Bacterial Toxins / Q000737:chemistry / Q000494:pharmacology*; D001980:Bronchi / Q000473:pathology; D002908:Chronic Disease; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D011014:Pneumonia / Q000150:complications / Q000382:microbiology / Q000473:pathology; D011549:Pseudomonas / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000150:complications / Q000382:microbiology / Q000473:pathology; D011710:Pyocyanine / Q000737:chemistry / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001427:Bacterial Toxins; D011710:Pyocyanine
keywords: EIF2AK4/GCN2; Pseudomonas aeruginosa; autophagy; lung; pathoadaptive mutations; pyocyanin