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Journal of Bacteriology, February 2002, p. 1132-1139, Vol. 184, No. 4
0021-9193/01/$04.00+0     DOI: 10.1128/jb.184.4.1132-1139.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Pseudomonas aeruginosa Quorum-Sensing Molecule N-(3-Oxododecanoyl)Homoserine Lactone Contributes to Virulence and Induces Inflammation In Vivo

Roger S. Smith,1 Sarah G. Harris,1,2 Richard Phipps,1,2 and Barbara Iglewski1*

Department of Microbiology and Immunology,1 James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 146422

Received 20 August 2001/ Accepted 29 October 2001

Pseudomonas aeruginosa has two well-characterized quorum-sensing systems, Las and Rhl. These systems are composed of LuxR-type proteins, LasR and RhlR, and two acyl homoserine lactone (AHL) synthases, LasI and RhlI. LasI catalyzes the synthesis of N-(3-oxododecanoyl)homoserine lactone (3O-C12-HSL), whereas RhlI catalyzes the synthesis of N-butyryl-homoserine lactone. There is little known about the importance of AHLs in vivo and what effects these molecules have on eukaryotic cells. In order to understand the role of AHLs in vivo, we first tested the effects that deletions of the synthase genes in P. aeruginosa had on colonization of the lung. We demonstrate that in an adult mouse acute-pneumonia model, deletion of the lasI gene or both the lasI and rhlI genes greatly diminished the ability of P. aeruginosa to colonize the lung. To determine whether AHLs have a direct effect on the host, we examined the effects of 3O-C12-HSL injected into the skin of mice. In this model, 3O-C12-HSL stimulated a significant induction of mRNAs for the cytokines interleukin-1{alpha} (IL-1{alpha}) and IL-6 and the chemokines macrophage inflammatory protein 2 (MIP-2), monocyte chemotactic protein 1, MIP-1ß, inducible protein 10, and T-cell activation gene 3. Additionally, dermal injections of 3O-C12-HSL also induced cyclooxygenase 2 (Cox-2) expression. The Cox-2 enzyme is important for the conversion of arachidonic acid to prostaglandins and is associated with edema, inflammatory infiltrate, fever, and pain. We also demonstrate that 3O-C12-HSL activates T cells to produce the inflammatory cytokine gamma interferon and therefore potentially promotes a Th1 environment. Induction of these inflammatory mediators in vivo is potentially responsible for the significant influx of white blood cells and subsequent tissue destruction associated with 3O-C12-HSL dermal injections. Therefore, the quorum-sensing systems of P. aeruginosa contribute to its pathogenesis both by regulating expression of virulence factors (exoenzymes and toxins) and by inducing inflammation.

* Corresponding author. Mailing address: Dept. of Microbiology and Immunology, Box 672, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642. Phone: (716) 275-3402. Fax: (716) 473-9573. E-mail: bigl{at}medinfo.rochester.edu.

Journal of Bacteriology, February 2002, p. 1132-1139, Vol. 184, No. 4
0021-9193/01/$04.00+0     DOI: 10.1128/jb.184.4.1132-1139.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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