The Journal of Experimental Medicine
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Published 1 July 2002. doi:10.1084/jem.20020005
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© Rockefeller University Press, 0022-1007/2002/7/109/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 1, July 1, 2002 109-118

Multidrug Efflux Systems Play an Important Role in the Invasiveness of Pseudomonas aeruginosa

Yoichi Hirakata1,6,7, Ramakrishnan Srikumar2, Keith Poole2, Naomasa Gotoh4, Takashi Suematsu5, Shigeru Kohno6, Shimeru Kamihira7, Robert E. W. Hancock3 and David P. Speert1

1 Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4 Canada
2 Department of Microbiology and Immunology, Queen's University, Kingston, Ontario K7L 3N6, Canada
3 Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
4 Department of Microbiology, Kyoto Pharmaceutical University, Kyoto, 607-8414 Japan
5 Central Electron Microscopy Laboratory, Nagasaki University School of Medicine, Nagasaki, 852-8501 Japan
6 Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, 852-8501 Japan
7 Department of Laboratory Medicine, Nagasaki University School of Medicine, Nagasaki, 852-8501 Japan

Address correspondence to Yoichi Hirakata, Dept. of Laboratory Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan. Phone: 81-95-849-7418; Fax: 81-95-849-7257; E-mail: hirakata{at}net.nagasaki-u.ac.jp

Pseudomonas aeruginosa is an important opportunistic human pathogen. Certain strains can transmigrate across epithelial cells, and their invasive phenotype is correlated with capacity to cause invasive human disease and fatal septicemia in mice. Four multidrug efflux systems have been described in P. aeruginosa, however, their contribution to virulence is unclear. To clarify the role of efflux systems in invasiveness, P. aeruginosa PAO1 wild-type (WT) and its efflux mutants were evaluated in a Madin-Darby canine kidney (MDCK) epithelial cell monolayer system and in a murine model of endogenous septicemia. All efflux mutants except a {Delta}mexCD-oprJ deletion demonstrated significantly reduced invasiveness compared with WT. In particular, a {Delta}mexAB-oprM deletion strain was compromised in its capacity to invade or transmigrate across MDCK cells, and could not kill mice, in contrast to WT which was highly invasive (P < 0.0006) and caused fatal infection (P < 0.0001). The other mutants, including {Delta}mexB and {Delta}mexXY mutants, were intermediate between WT and the {Delta}mexAB-oprM mutant in invasiveness and murine virulence. Invasiveness was restored to the {Delta}mexAB-oprM mutant by complementation with mexAB-oprM or by addition of culture supernatant from MDCK cells infected with WT. We conclude that the P. aeruginosa MexAB-OprM efflux system exports virulence determinants that contribute to bacterial virulence.

Key Words: Pseudomonas aeruginosa • bacterial invasion • multidrug efflux system • outer membrane protein • endogenous bacteremia


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