Maintenance of Paraoxonase 2 Activity as a Strategy to Attenuate P. Aeruginosa Virulence
Abstract
The P.aeruginosa signaling and virulence molecule 3OC12 mediates inactivation of the lactonase paraoxonase 2 (PON2) and induces many immunomodulatory effects in host cells. Because PON2 rapidly inactivates 3OC12, we hypothesized that preventing PON2 inactivation by 3OC12 could be a viable therapeutic strategy to limit P.aeruginosa quorum signaling and thereby attenuate virulence. We demonstrated in both human and mouse primary cell types that PON2 is sensitive to 3OC12-mediated inactivation at concentrations of 3OC12 expected to be present near P.aeruginosa colonies during infection. We also discovered that 3OC12 is rapidly hydrolyzed intracellularly by PON2 to 3OC12-acid, which becomes trapped and accumulates within the cells. 3OC12 caused a rapid cytosolic pH decrease, calcium release and phosphorylation of stress signaling kinases. All of these effects were dependent upon PON2 activity. A potent PON2 inhibitor was also identified and treatment of cells with the inhibitor prevented 3OC12-mediated inactivation of PON2. The findings suggest the intracellular acidification is that proximal event that mediates both PON2 inactivation and many immunomodulatory effects of 3OC12. Thus, protecting cells from 3OC12-mediated acidification could be an important therapeutic strategy to attenuate P.aeruginosa quorum signaling and virulence in infected individuals.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2013
- Accession Number
- ADA599512
Entities
People
- John F. Teiber
Organizations
- University of Texas at Dallas