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Pseudomonas aeruginosa  infection can be disastrous in chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. Its toxic effects are largely mediated by secreted virulence factors including pyocyanin, elastase and alkaline protease (AprA). Efficient functioning of the endoplasmic reticulum (ER) is crucial for cell survival and appropriate immune responses, while an excess of unfolded proteins within the ER leads to “ER stress” and activation of the “unfolded protein response” (UPR). Bacterial infection and Toll-like receptor activation trigger the UPR most likely due to the increased demand for protein folding of inflammatory mediators. In this study, we show that cell-free conditioned medium of the PAO1 strain of  P .  aeruginosa , containing secreted virulence factors, induces ER stress in primary bronchial epithelial cells as evidenced by splicing of  XBP1  mRNA and induction of  CHOP ,  GRP78  and  GADD34  expression. Most aspects of the ER stress response were dependent on TAK1 and p38 MAPK, except for the induction of  GADD34  mRNA. Using various mutant strains and purified virulence factors, we identified pyocyanin and AprA as inducers of ER stress. However, the induction of  GADD34  was mediated by an ER stress-independent integrated stress response (ISR) which was at least partly dependent on the iron-sensing eIF2α kinase HRI. Our data strongly suggest that this increased  GADD34  expression served to protect against  Pseudomonas -induced, iron-sensitive cell cytotoxicity. In summary, virulence factors from  P .  aeruginosa  induce ER stress in airway epithelial cells and also trigger the ISR to improve cell survival of the host.

Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells