Maintenance of Paraoxonase 2 Activity as a Strategy to Attenuate P. Aeruginosa Virulence
Abstract
The P. aeruginosa signaling/virulence molecule 3OC12 mediates inactivation of the lactonase paraoxonase 2 (PON2) and induces immunomodulatory effects in host cells. Because PON2 rapidly inactivates 3OC12, we hypothesized that preventing PON2 inactivation by 3OC12 could be a therapeutic strategy to limit P. aeruginosa signaling and thereby attenuate virulence. In human primary cell types PON2 was sensitive to 3OC12-mediated inactivation at 3OC12 concentrations expected to be present near P. aeruginosa colonies during infection. In mouse primary cell types PON2 was not as sensitive to 3OC12-mediated inactivation as in human cells. We also discovered that 3OC12 is rapidly hydrolyzed intracellularly by PON2 to 3OC12-acid, which becomes trapped and accumulates within the cells, specifically within the endoplasmic reticulum (ER) and mitochondria. 3OC12 caused a rapid PON2-dependent cytosolic and mitochondrial pH decrease, calcium release and phosphorylation of stress signaling kinases. Findings suggest that intracellular acidification is the proximal event that mediates many immunomodulatory effects of 3OC12 and PON2 inactivation. PON2 appears to be inactivated by 3OC12 via an ER stress-like response triggered by acidification. Two compounds were identified that inhibit acidification and PON2 inactivation, suggesting that they could be model drugs to prevent 3OC12-mediated biological effects. Protecting cells from 3OC12-mediated acidification could be an important therapeutic strategy to attenuate P. aeruginosa virulence and host cell immunomodulation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2015
- Accession Number
- AD1003001
Entities
People
- John F. Teiber
Organizations
- University of Texas Southwestern Medical Center