| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Japan;
Department of Microbiology, Tokyo Medical University School of Medicine, Tokyo, Japan;
Section of Retroviral Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892;
Department of Host Defense, Research Institute for Microbial Diseases, Osaka, Japan;
¶ Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka, Japan; and Exploratory Research for Advanced Technology, Akira Innate Immunity Project, Japan Science and Technology Agency, Osaka, Japan
Flagellin is a key component of the flagella of many pathogens, including Pseudomonas aeruginosa. Flagellin is an attractive vaccine candidate because it is readily produced and manipulated as a recombinant protein and has intrinsic adjuvant activity mediated through TLR5. Although DNA vaccines encoding native Pseudomonas B-type (FliC) or A-type (FlaA) flagellin are strongly immunogenic, the resultant Ab response interferes with the interaction of homologous flagellin with TLR5. This reduces the ability of the host to clear homologous, but not heterologous, flagellin-expressing P. aeruginosa. To circumvent this problem, a DNA vaccine encoding a mutant FliC R90A flagellin was developed. The mutant Ag encoded by this vaccine was highly immunogenic, but its ability to interact with TLR5 was reduced by >100-fold. Vaccination with this flagellin mutant DNA vaccine induced cross-reactive Abs against both FliC and FlaA, but few Abs capable of interfering with TLR5 activation. The flagellin mutant DNA vaccine provided excellent protection against both FliC- and FlaA-expressing P. aeruginosa. These findings suggest that vaccines against flagellated pathogens should avoid inducing Abs against TLR5 and raise the possibility that flagellated bacteria evade host elimination by facilitating the production of Abs that reduce the host’s ability to mount an innate immune response.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and the Yokohama Medical Foundation (Yokohama City University Center of Excellence Program to N.J., 18590432 to F.T., and 18659126 to K.O.), the National Institute of Biomedical Innovation (to K.O.), Strategic Research Project of Yokohama City University (K18022 to F.T.), Advancement of Medical Sciences from Yokohama Medical Foundation (to F.T.), and Japan Science and Technology Agency (131-1 to F.T.).
2 S.S. and F.T. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Fumihiko Takeshita, Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. E-mail address: takesita{at}yokohama-cu.ac.jp
4 Abbreviations used in this paper: FlaA, A-type flagellin; WT, wild type; FliC, B-type flagellin; p.i., postinfection; MPO, myeloperoxidase.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
