title: Rabies virus expressing dendritic cell-activating molecules enhances the innate and adaptive immune response to vaccination.
abstract: Our previous studies indicated that recruitment and/or activation of dendritic cells (DCs) is important in enhancing the protective immune responses against rabies virus (RABV) (L. Zhao, H. Toriumi, H. Wang, Y. Kuang, X. Guo, K. Morimoto, and Z. F. Fu, J. Virol. 84:9642-9648). To address the importance of DC activation for RABV vaccine efficacy, the genes for several DC recruitment and/or activation molecules, e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage-derived chemokine (MDC), and macrophage inflammatory protein 1α (MIP-1α), were individually cloned into RABV. The ability of these recombinant viruses to activate DCs was determined in vitro and in vivo. Infection of mouse bone marrow-derived DCs with each of the recombinant viruses resulted in DC activation, as shown by increased surface expression of CD11c and CD86 as well as an increased level of alpha interferon (IFN-α) production compared to levels observed after infection with the parent virus. Intramuscular infection of mice with each of the viruses recruited and/or activated more DCs and B cells in the periphery than infection with the parent virus, leading to the production of higher levels of virus-neutralizing antibodies. Furthermore, a single immunization with recombinant RABV expressing GM-CSF or MDC protected significantly more mice against intracerebral challenge with virulent RABV than did immunization with the parental virus. Yet, these viruses did not show more virulence than the parent virus, since direct intracerebral inoculation with each virus at up to 1 × 10(7) fluorescent focus units each did not induce any overt clinic symptom, such as abnormal behavior, or any neurological signs. Together, these data indicate that recombinant RABVs expressing these molecules activate/recruit DCs and enhance protective immune responses.
authors.affiliation: Department of Pathology, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wen
authors.forename: Hualei
authors.initials: H
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.forename: Fuhe
authors.initials: F
authors.lastname: Yang
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Tripp
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hogan
authors.forename: Zhen F
authors.initials: ZF
authors.lastname: Fu
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D054422:Chemokine CCL22 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054405:Chemokine CCL3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006224:Cricetinae; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D011818:Rabies / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D011819:Rabies Vaccines / Q000235:genetics / Q000276:immunology*; D011820:Rabies virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D011995:Recombination, Genetic; D014611:Vaccination
chemical_list: D054422:Chemokine CCL22; D054405:Chemokine CCL3; D018925:Chemokines; D011819:Rabies Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor