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J Med Microbiol 55 (2006), 1381-1387; DOI: 10.1099/jmm.0.46658-0
© 2006 Society for General Microbiology
ISSN 1473-5644

Immunization with 3-oxododecanoyl-L-homoserine lactone–protein conjugate protects mice from lethal Pseudomonas aeruginosa lung infection

Shinichi Miyairi1, Kazuhiro Tateda2, Etsu T. Fuse2, Chihiro Ueda1, Hiroaki Saito1, Tohru Takabatake1, Yoshikazu Ishii2, Manabu Horikawa3, Masaji Ishiguro3, Theodore J. Standiford4 and Keizo Yamaguchi2

1 Laboratory of Bio-organic Chemistry, College of Pharmacy, Nihon University, Chiba 274-8555, Japan

2 Departments of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo 143-8540, Japan

3 Suntory Institute for Bioorganic Research, Osaka 618-8503, Japan

4 Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0360, USA

Correspondence
Kazuhiro Tateda
kazu{at}med.toho-u.ac.jp

Received 4 April 2006
Accepted 21 June 2006

Quorum-sensing systems have been reported to play a critical role in the pathogenesis of several bacterial infections. Recent data have demonstrated that Pseudomonas N-3-oxododecanoyl-L-homoserine lactone (3-oxo-C12-homoserine lactone, 3-oxo-C12-HSL), but not N-butanoyl-L-homoserine lactone (C4-HSL), induces apoptosis in macrophages and neutrophils. In the present study, the effects of active immunization with 3-oxo-C12-HSL–carrier protein conjugate on acute P. aeruginosa lung infection in mice were investigated. Immunization with 3-oxo-C12-HSL–BSA conjugate (subcutaneous, four times, at 2-week intervals) elaborated significant amounts of specific antibody in serum. Control and immunized mice were intranasally challenged with approximately 3x106 c.f.u. P. aeruginosa PAO1, and survival was then compared. All control mice died by day 2 post bacterial challenge, while 36 % of immunized mice survived to day 4 (P<0.05). Interestingly, bacterial numbers in the lungs did not differ between control and immunized groups, whereas the levels of pulmonary tumour necrosis factor (TNF)-{alpha} in the immunized mice were significantly lower than those of control mice (P<0.05). Furthermore, the extractable 3-oxo-C12-HSL levels in serum and lung homogenate were also significantly diminished in the immunized mice. Immune serum completely rescued reduction of cell viability by 3-oxo-C12-HSL-mediated apoptosis in macrophages in vitro. These results demonstrated that specific antibody to 3-oxo-C12-HSL plays a protective role in acute P. aeruginosa infection, probably through blocking of host inflammatory responses, without altering lung bacterial burden. The present data identify a promising potential vaccine strategy targeting bacterial quorum-sensing molecules, including autoinducers.

Abbreviations: C4-HSL, N-butanoyl-L-homoserine lactone; HRP, horseradish peroxidase; HSL, homoserine lactone; IL, interleukin; OV, ovalbumin; 3-oxo-C12-HSL, N-3-oxododecanoyl-L-homoserine lactone; TNF, tumour necrosis factor.




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