Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium

Abstract

Ferroptosis is a death program executed via selective oxidation of arachidonic acid-phosphatidylethanolamines (AA-PE) by 15-lipoxygenases. In mammalian cells and tissues, ferroptosis has been pathogenically associated with brain, kidney, and liver injury/diseases. We discovered that a prokaryotic bacterium, Pseudomonas aeruginosa, that does not contain AA-PE can express lipoxygenase (pLoxA), oxidize host AA-PE to 15-hydroperoxy-AA-PE (15-HOO-AA-PE), and trigger ferroptosis in human bronchial epithelial cells. Induction of ferroptosis by clinical P. aeruginosa isolates from patients with persistent lower respiratory tract infections was dependent on the level and enzymatic activity of pLoxA. Redox phospholipidomics revealed elevated levels of oxidized AA-PE in airway tissues from patients with cystic fibrosis (CF) but not with emphysema or CF without P. aeruginosa. We believe that the evolutionarily conserved mechanism of pLoxA-driven ferroptosis may represent a potential therapeutic target against P. aeruginosa-associated diseases such as CF and persistent lower respiratory tract infections.

RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer

“…Ferroptosis is dependent upon intracellular iron, and is a new cell death form distinct from necrosis, autophagy, and apoptosis ( Dar et al, 2018 ; Gao et al, 2018 ). Ferroptosis is tightly controlled by GPX4 and some iron transport regulatory proteins ( Feng and Stockwell, 2018 ).…”

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

“…As noted above, complex formation between 15‐LOX and PEBP1 may act in some models to specifically promote the proferroptotic oxidation of polyunsaturated phosphatidylethanolamines . LOX orthologs secreted by Pseudomonas aeruginosa can also trigger PUFA‐PE oxidation and “theft ferroptosis” in host epithelial cells . It has also been proposed that vitamin E may inhibit ferroptosis not merely as a general lipophilic antioxidant, but as a specific inhibitor of 15‐LOX enzyme activity .…”

Cross talk between intracellular pathogens and cell death

“…Dar and colleagues, for example, recently reported that during lung infection with Pseudomonas aeruginosa, the bacteria can express and release lipoxygenase (pLoxA) which oxidizes host arachidonic acid‐phosphatidylethanolamines (AA‐PE) to 15‐hydroperoxy‐AA‐PE (15‐HOO‐AA‐PE), and thereby induce ferroptotic death of human bronchial epithelial cells 91 . While the importance of pLoxA for bacterial virulence was not studied in vivo, it could be implied from other experiments that detected oxidized AA‐PE in airway tissues from P. aeruginosa ‐infected cystic fibrosis patients 91 . Another recent study revealed that the necrosis of macrophages that was commonly observed during Mycobacterium tuberculosis infections is caused by ferroptosis 92 .…”