title: Rabies virus lipopeptide conjugated to a TLR7 agonist improves the magnitude and quality of the Th1-biased humoral immune response in mice.
abstract: In this study, we conjugated the rabies-derived lipopeptide CE536 to a TLR7 agonist, imiquimod, and evaluated its adjuvanticity. The synthetic construct (Lipo-I) targeted to TLR7, induced dendritic cell phenotypic maturation and production of both type I interferon and pro-inflammatory cytokines more efficiently than unconjugated TLR7 ligands or lipopeptide alone. The immunostimulatory effects of the conjugate were apparently the result of IκBα degradation and sustained p38 and JNK phosphorylation. The analysis of IgG isotypes and T cell differentiation showed that IgG2a dominant Th1-biased humoral and CD8(+) IFN-γ T cell responses were induced by Lipo-I. Lipo-I could facilitate the rabies vaccine to induce the production of an earlier and more vigorous rabies virus neutralizing antibody. In the post-exposure test, the Lipo-I adjuvanted vaccine provided a 73.3% survival rate, while the traditional vaccine bestowed only a 26.7% survival. Therefore, Lipo-I is a promising adjuvant for the development of more effective rabies vaccines.
authors.affiliation: Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China. Electronic address: ruiliu12@fudan.edu.cn.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Inamullah
authors.initials: I
authors.lastname: Khan
authors.affiliation: Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Naishuo
authors.initials: N
authors.lastname: Zhu
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D056724:Immunity, Humoral; D007113:Immunity, Innate; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D055666:Lipopeptides / Q000276:immunology*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011818:Rabies / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D011819:Rabies Vaccines / Q000276:immunology; D011820:Rabies virus / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: D000276:Adjuvants, Immunologic; D000956:Antigens, Viral; D016207:Cytokines; D018796:Immunoconjugates; D055666:Lipopeptides; D016328:NF-kappa B; D011819:Rabies Vaccines; D051199:Toll-Like Receptor 7; D020928:Mitogen-Activated Protein Kinases
keywords: Adjuvant; Imiquimod; Lipopeptide; Rabies vaccine; TLR7