Drosophila are protected from Pseudomonas aeruginosa lethality by transgenic expression of paraoxonase-1

Abstract

Pseudomonas aeruginosa uses quorum sensing, an interbacterial communication system, to regulate gene expression. The signaling molecule N-3-oxododecanoyl homoserine lactone (3OC12-HSL) is thought to play a central role in quorum sensing. Since 3OC12-HSL can be degraded by paraoxonase (PON) family members, we hypothesized that PONs regulate P. aeruginosa virulence in vivo. We chose Drosophila melanogaster as our model organism because it has been shown to be a tractable model for investigating host-pathogen interactions and lacks PONs. By using quorum-sensing-deficient P. aeruginosa, synthetic acyl-HSLs, and transgenic expression of human PON1, we investigated the role of 3OC12-HSL and PON1 on P. aeruginosa virulence. We found that P. aeruginosa virulence in flies was dependent upon 3OC12-HSL. PON1 transgenic flies expressed enzymatically active PON1 and thereby exhibited arylesterase activity and resistance to organophosphate toxicity. Moreover, PON1 flies were protected from P. aeruginosa lethality, and protection was dependent on the lactonase activity of PON1. Our findings show that PON1 can interfere with quorum sensing in vivo and provide insight into what we believe is a novel role for PON1 in the innate immune response to quorum-sensing-dependent pathogens. These results raise intriguing possibilities about human-pathogen interactions, including potential roles for PON1 as a modifier gene and for PON1 protein as a regulator of normal bacterial florae, a link between infection/inflammation and cardiovascular disease, and a potential therapeutic modality.

Functionality of HDL: Antioxidation and Detoxifying Effects

“…The ability of the PON enzymes to hydrolyse the HSL interrupts bacterial communication and reduces virulence. Whilst the intracellular PON2 variant shows the strongest lactonase activity, PON1is also active towards HSL (Ozer et al 2005) and is able to protect against Pseudomonas infection (Stoltz et al 2008). Indeed, PON1 is the major source of HSL neutralising activity in serum (Teiber et al 2008).…”

Novel common and rare genetic determinants of paraoxonase activity: FTO, SERPINA12, and ITGAL

“…Like HDL ( 65,66 ), PON1 is an acute phase reactant and has been associated with the immune response ( 67,68 ) and infl ammation ( 69 ). Specifi cally, PON1 has been demonstrated to be a host modulator of Pseudomonas aeruginosa quorum sensing ( 35 ), with transgenic expression of PON1 being protective in Drosophila from infection lethality ( 36 ). Therefore, the fi nding of ITGAL SNP rs1557672 being associated with a decrease in PON1 activity ( ␤ coeffi cient = Ϫ 7.16) may indicate a further role of immune regulation of HDL, and specifically, PON1 activity.…”

Inhibition of quorum sensing-controlled virulence factors in Pseudomonas aeruginosa by human serum paraoxonase

“…The lactonase activity of PON enzymes led to the hypothesis that they may also play a role in the attenuation of bacterial virulence by interfering with QS (Camps et al, 2011). In line with this hypothesis, it has been shown that overexpression of PON2 increases AHL inactivation in human airway epithelial cell lysates (Stoltz et al, 2008); additionally, of the three PON enzymes, PON2 exhibits the highest activity towards the important AHL, N-3-oxododecanoyl homoserine lactone (3OC12HSL). It has also been demonstrated that both PON1 and PON2 are important for the control of P. aeruginosa QS (Ozer et al, 2005;Teiber et al, 2008).…”