Processing of lysophosphatidylcholines by ExoU secreted by P. aeruginosa leads to inflammasome activation and cell death

Pseudomonas aeruginosa (P. aeruginosa) thrives in the lungs of patients with cystic fibrosis (CF) which results in pulmonary inflammation and decline in lung function. Inflammasome signaling promotes host cell death and processing of IL-1 which results in bacterial control. Since the type 3 secretion system (T3SS) of P. aeruginosa induces inflammasome signaling, we evaluated the role of ExoU, a phospholipase which is secreted through the T3SS and promotes host susceptibility. Our results indicate that the genes associated with T3SS-function display increased polymorphism and are poorly expressed in the chronic isolates of P. aeruginosa from patients with CF, which leads to poor inflammasome activation. ExoU, secreted by P. aeruginosa modulates the lipidome of infected cells extensively, which results in an increase in the intracellular levels of lysophosphatidylcholine species that leads to the activation of NF-κB and MAPK pathways and cell death by inflammasome signaling, which is inhibited by lysophosphatidylcholine acyltransferase 3 (LPCAT3).