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Drosophila are protected from Pseudomonas aeruginosa lethality by transgenic expression of paraoxonase-1
David A. Stoltz, … , Matthew R. Parsek, Joseph Zabner
David A. Stoltz, … , Matthew R. Parsek, Joseph Zabner
Published August 14, 2008
Citation Information: J Clin Invest. 2008;118(9):3123-3131. https://doi.org/10.1172/JCI35147.
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Research Article Infectious disease Article has an altmetric score of 3

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

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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.

Authors

David A. Stoltz, Egon A. Ozer, Peter J. Taft, Marilyn Barry, Lei Liu, Peter J. Kiss, Thomas O. Moninger, Matthew R. Parsek, Joseph Zabner

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Figure 1

Quorum-sensing–dependent P. aeruginosa infection of Drosophila.

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Quorum-sensing–dependent P. aeruginosa infection of Drosophila.
   
(A a...
(A and B) Scanning electron micrographs at low and high magnification of Drosophila at 24 hours following infection with wild-type P. aeruginosa (PAO1). (A) Low-magnification image shows a whole fly with an opening in the distal abdomen. Scale bar: 0.5 mm. (B) High-magnification image of boxed area on whole fly. Arrow indicates bacteria and asterisk denotes extracellular matrix. Scale bar: 2.5 μm. (C and D) GFP signal (quorum-sensing activity) after infection of Drosophila with a quorum-sensing reporter strain of P. aeruginosa (under control of the lasB promoter). GFP signal at 0 hours (C) and 18 hours (D) following abdominal inoculation with PAO1. Scale bars: 0.5 mm. (E) Fly survival after infection with PAO1 and quorum-sensing–deficient strains of P. aeruginosa. da-GAL4/+ flies were infected with PAO1 (squares), ΔlasI/rhlI (circles), or ΔlasR/rhlR (triangles) strains. n = 30 flies per group for each experiment. *P < 0.001, comparing PAO1 versus ΔlasI/rhlI and PAO1 versus ΔlasR/rhlR fly survival; log-rank test. (F) P. aeruginosa bacterial counts after infection with PAO1 or ΔlasI/rhlI. At 6, 12, and 18 hours following infection, flies were anesthetized, surface sterilized, and homogenized for performance of quantitative bacterial counts. Data are displayed as log10 CFU/fly and represent the mean ± SEM. n = 3–5 per time point with 10–20 flies per group per experiment.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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