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Journal of Virology, July 2006, p. 6218-6224, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.00121-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor Adaptor Molecules Enhance DNA-Raised Adaptive Immune Responses against Influenza and Tumors through Activation of Innate Immunity

Fumihiko Takeshita,1* Toshiyuki Tanaka,1 Tomoko Matsuda,1 Miyuki Tozuka,1 Kouji Kobiyama,1 Sukumar Saha,1 Kiyohiko Matsui,1 Ken J. Ishii,2 Cevayir Coban,2 Shizuo Akira,2 Norihisa Ishii,3 Koichi Suzuki,3 Dennis M. Klinman,4 Kenji Okuda,1 and Shin Sasaki1

Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan,1 ERATO, Akira Innate Immunity Program, Japan Science and Technology Agency, Osaka 565-0871, Japan,2 Department of Bioregulation, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo 189-0002, Japan,3 Section of Retroviral Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 208924

Received 18 January 2006/ Accepted 12 April 2006

Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates the innate and adaptive immunity. TLR adaptor molecules play a central role in this cascade; thus, we hypothesized that overexpression of TLR adaptor molecules could mimic infection without any microbial components. Dual-promoter plasmids that carry an antigen and a TLR adaptor molecule such as the Toll-interleukin-1 receptor domain-containing adaptor-inducing beta interferon (TRIF) or myeloid differentiation factor 88 (MyD88) were constructed and administered to mice to determine if these molecules can act as an adjuvant. A DNA vaccine incorporated with the MyD88 genetic adjuvant enhanced antigen-specific humoral immune responses, whereas that with the TRIF genetic adjuvant enhanced cellular immune responses. Incorporating the TRIF genetic adjuvant in a DNA vaccine targeting the influenza HA antigen or the tumor-associated antigen E7 conferred superior protection. These results indicate that TLR adaptor molecules can bridge innate and adaptive immunity and potentiate the effects of DNA vaccines against virus infection and tumors.

* Corresponding author. Mailing address: Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama 236-0004, Japan. Phone: 81-45-787-2602. Fax: 81-45-787-2851. E-mail: takesita{at}yokohama-cu.ac.jp.

Journal of Virology, July 2006, p. 6218-6224, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.00121-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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