Pseudomonas toxin pyocyanin triggers autophagy: Implications for pathoadaptive mutations

Autophagy. 2016 Jun 2;12(6):1015-28. doi: 10.1080/15548627.2016.1170256. Epub 2016 May 9.

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.

Keywords: EIF2AK4/GCN2; Pseudomonas aeruginosa; autophagy; lung; pathoadaptive mutations; pyocyanin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological*
  • Animals
  • Autophagosomes / drug effects
  • Autophagosomes / metabolism
  • Autophagy / drug effects*
  • Bacterial Toxins / chemistry
  • Bacterial Toxins / pharmacology*
  • Bronchi / pathology
  • Chronic Disease
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / ultrastructure
  • Humans
  • Inflammation / complications
  • Inflammation / pathology
  • Mutation / genetics*
  • Pneumonia / complications
  • Pneumonia / microbiology
  • Pneumonia / pathology
  • Pseudomonas / metabolism*
  • Pseudomonas Infections / complications
  • Pseudomonas Infections / microbiology
  • Pseudomonas Infections / pathology
  • Pyocyanine / chemistry
  • Pyocyanine / pharmacology*
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects

Substances

  • Bacterial Toxins
  • Pyocyanine