Immunization with 3-oxododecanoyl-L-homoserine lactone-protein conjugate protects mice from lethal Pseudomonas aeruginosa lung infection.
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 3 x 10(6) 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.
Miyairi
Shinichi
S
Laboratory of Bio-organic Chemistry, College of Pharmacy, Nihon University, Chiba 274-8555, Japan.
Tateda
Kazuhiro
K
Departments of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo 143-8540, Japan.
Fuse
Etsu T
ET
Departments of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo 143-8540, Japan.
Ueda
Chihiro
C
Laboratory of Bio-organic Chemistry, College of Pharmacy, Nihon University, Chiba 274-8555, Japan.
Saito
Hiroaki
H
Laboratory of Bio-organic Chemistry, College of Pharmacy, Nihon University, Chiba 274-8555, Japan.
Takabatake
Tohru
T
Laboratory of Bio-organic Chemistry, College of Pharmacy, Nihon University, Chiba 274-8555, Japan.
Ishii
Yoshikazu
Y
Departments of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo 143-8540, Japan.
Horikawa
Manabu
M
Suntory Institute for Bioorganic Research, Osaka 618-8503, Japan.
Ishiguro
Masaji
M
Suntory Institute for Bioorganic Research, Osaka 618-8503, Japan.
Standiford
Theodore J
TJ
Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0360, USA.
Yamaguchi
Keizo
K
Departments of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo 143-8540, Japan.
D015107:4-Butyrolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000276:immunology; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D015169:Colony Count, Microbial; D006714:Homoserine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000276:immunology; D007106:Immune Sera / Q000494:pharmacology; D007279:Injections, Subcutaneous; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018410:Pneumonia, Bacterial / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D011552:Pseudomonas Infections / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000302:isolation & purification; D012710:Serum Albumin, Bovine / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism; D014611:Vaccination; D018074:Vaccines, Conjugate / Q000008:administration & dosage; D014614:Vaccines, Synthetic
D000907:Antibodies, Bacterial; D007106:Immune Sera; C109860:N-(3-oxododecanoyl)homoserine lactone; D014409:Tumor Necrosis Factor-alpha; D018074:Vaccines, Conjugate; D014614:Vaccines, Synthetic; C088386:homoserine lactone; D012710:Serum Albumin, Bovine; D006714:Homoserine; D015107:4-Butyrolactone