title: Toll-like receptor adaptor molecules enhance DNA-raised adaptive immune responses against influenza and tumors through activation of innate immunity.
abstract: 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.
authors.affiliation: Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama 236-0004, Japan. takesita@yokohama-cu.ac.jp
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeshita
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tomoko
authors.initials: T
authors.lastname: Matsuda
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tozuka
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.forename: Sukumar
authors.initials: S
authors.lastname: Saha
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Matsui
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Cevayir
authors.initials: C
authors.lastname: Coban
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishii
authors.forename: Koichi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
authors.forename: Kenji
authors.initials: K
authors.lastname: Okuda
authors.forename: Shin
authors.initials: S
authors.lastname: Sasaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000235:genetics; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007114:Immunization; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000276:Adjuvants, Immunologic; D000956:Antigens, Viral; D019496:Cancer Vaccines; D007252:Influenza Vaccines; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D050725:Papillomavirus E7 Proteins; C470409:TICAM1 protein, human; D019444:Vaccines, DNA