Translocation of Pyoverdine into Host Cells Mediates Iron Removal and Activates a Specific Host Immune Response

Pseudomonas aeruginosa is a re-emerging opportunistic pathogen with broad antimicrobial resistance. We have previously reported that the major siderophore pyoverdine from this pathogen disrupts mitochondrial networks and induces a lethal hypoxic response in model host Caernorhabditis elegans. However, the mechanism of such cytotoxicity remained unclear. Here, we demonstrate that pyoverdine translocates into host cells, binding to host ferric iron sources. The reduction of host iron content disrupts mitochondrial function such as NADH oxidation and ATP production and activates mitophagy. This activates a specific immune response that is distinct from colonization-based pathogensis and exposure to downstream pyoverdine effector Exotoxin A. Host response to pyoverdine resembles that of a hypoxic crisis or iron chelator treatment. Furthermore, we demonstrate that pyoverdine is a crucial virulence factor in P. aerguinosa pathogenesis against cystic fibrosis patients; ΔF508 mutation in human CFTR increases susceptibility to pyoverdine-mediated damage. There are 9 samples total that comprise three biological replicates of glp-4 animals exposed to S basal media or pyoverdine in liquid for 12 hours at 25°C, or left untreated on original agar plates. Each biological replicate consists of glp-4 C. elegans animals in the young adult developmental stage.