title: The inability of wild-type rabies virus to activate dendritic cells is dependent on the glycoprotein and correlates with its low level of the de novo-synthesized leader RNA.
abstract: Dendritic cells (DCs) are the most efficient antigen-presenting cells, playing a key role in the adaptive immune responses to viral infections. Our studies demonstrate that wild-type (wt) rabies virus (RABV) does not activate DCs. Adoptive transfer of DCs primed with wt RABV did not activate DCs, stimulate virus neutralizing antibodies (VNA), or protect recipients against challenge. However, adoptive transfer of DCs primed with laboratory-attenuated RABV resulted in DC activation, production of VNA, and protection against challenge. In vitro studies with recombinant RABV (laboratory-attenuated RABV expressing the glycoprotein or the phosphoprotein from wt RABV) demonstrate that DC activation is dependent on the glycoprotein and involves the IPS-1 pathway. Furthermore, binding to and entry into DCs by wt RABV is severely blocked, and the copy number of de novo-synthesized leader RNA was two logs lower in DCs infected with the wt than in DCs treated with laboratory-attenuated RABV. However, transient transfection of DCs with synthesized leader RNA from either wt or attenuated RABV is capable of activating DCs in a dose-dependent manner. Thus, the inability of wt RABV to activate DCs correlates with its low level of the de novo-synthesized leader RNA.
  
  
  OBJECTIVE
  Rabies remains a public health threat, with more than 55,000 fatalities each year around the world. Since DCs play a key role in the adaptive immune responses to viral infections, we investigated the ability of rabies virus (RABV) to activate DCs. It was found that the adoptive transfer of DCs primed with wt RABV did not activate DCs, stimulate VNA, or protect mice against lethal challenge. However, laboratory-attenuated RABV mediates the activation of DCs via the IPS-1 pathway and is glycoprotein dependent. We further show that wt RABV evades DC-mediated immune activation by inefficient binding/entry into DCs and as a result of a reduced level of de novo-synthesized leader RNA. These findings may have important implications in the development of efficient rabies vaccines.
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.
authors.forename: Clement W
authors.initials: CW
authors.lastname: Gnanadurai
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
authors.forename: Shengbo
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China cuimin@mail.hzau.edu.cn zhenfu@uga.edu.
authors.forename: Min
authors.initials: M
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA cuimin@mail.hzau.edu.cn zhenfu@uga.edu.
authors.forename: Zhen F
authors.initials: ZF
authors.lastname: Fu
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D006023:Glycoproteins / Q000276:immunology*; D008807:Mice, Inbred BALB C; D012367:RNA, Viral / Q000235:genetics; D011820:Rabies virus / Q000276:immunology*
chemical_list: D020121:5' Untranslated Regions; D006023:Glycoproteins; D012367:RNA, Viral