title: Interspecies protein substitution to investigate the role of the lyssavirus glycoprotein.
abstract: European bat lyssaviruses type 1 (EBLV-1) and type 2 (EBLV-2) circulate within bat populations throughout Europe and are capable of causing disease indistinguishable from that caused by classical rabies virus (RABV). However, the determinants of viral fitness and pathogenicity are poorly understood. Full-length genome clones based on the highly attenuated, non-neuroinvasive, RABV vaccine strain (SAD-B19) were constructed with the glycoprotein (G) of either SAD-B19 (SN), of EBLV-1 (SN-1) or EBLV-2 (SN-2). In vitro characterization of SN-1 and SN-2 in comparison to wild-type EBLVs demonstrated that the substitution of G affected the final virus titre and antigenicity. In vivo, following peripheral infection with a high viral dose (10(4) f.f.u.), animals infected with SN-1 had reduced survivorship relative to infection with SN, resulting in survivorship similar to animals infected with EBLV-1. The histopathological changes and antigen distribution observed for SN-1 were more representative of those observed with SN than with EBLV-1. EBLV-2 was unable to achieve a titre equivalent to that of the other viruses. Therefore, a reduced-dose experiment (10(3) f.f.u.) was undertaken in vivo to compare EBLV-2 and SN-2, which resulted in 100 % survivorship for all recombinant viruses (SN, SN-1 and SN-2) while clinical disease developed in mice infected with the EBLVs. These data indicate that interspecies replacement of G has an effect on virus titre in vitro, probably as a result of suboptimal G-matrix protein interactions, and influences the survival outcome following a peripheral challenge with a high virus titre in mice.
authors.affiliation: Wildlife Zoonoses and Vector-borne Diseases Research Group, Animal Health and Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT15 3NB, UK.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Marston
authors.affiliation: University of Liverpool, National Consortium for Zoonosis Research, Leahurst, Neston, South Wirral, CH64 7TE, UK.|Wildlife Zoonoses and Vector-borne Diseases Research Group, Animal Health and Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT15 3NB, UK.
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: McElhinney
authors.affiliation: Wildlife Zoonoses and Vector-borne Diseases Research Group, Animal Health and Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT15 3NB, UK.
authors.forename: Ashley C
authors.initials: AC
authors.lastname: Banyard
authors.affiliation: Wildlife Zoonoses and Vector-borne Diseases Research Group, Animal Health and Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT15 3NB, UK.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Horton
authors.affiliation: Pathology Unit, Animal Health and Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT15 3NB, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Núñez
authors.affiliation: Department of Microbiology and Immunology, Jefferson Vaccine Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Koser
authors.affiliation: Department of Microbiology and Immunology, Jefferson Vaccine Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Schnell
authors.affiliation: University of Liverpool, National Consortium for Zoonosis Research, Leahurst, Neston, South Wirral, CH64 7TE, UK.|Wildlife Zoonoses and Vector-borne Diseases Research Group, Animal Health and Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT15 3NB, UK.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Fooks
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006651:Histocytochemistry; D007150:Immunohistochemistry; D018114:Lyssavirus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity*; D051379:Mice; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011995:Recombination, Genetic; D018353:Rhabdoviridae Infections / Q000473:pathology / Q000821:virology; D016019:Survival Analysis; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000956:Antigens, Viral; D006023:Glycoproteins; D011994:Recombinant Proteins; D014764:Viral Proteins; D037521:Virulence Factors