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/eIF2a ATF4 pathway. Interestingly, rats infected with the phzMD 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 phzMD 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.
Autophagy