title: Reinvestigation of the role of the rabies virus glycoprotein in viral pathogenesis using a reverse genetics approach.
abstract: The rabies virus glycoprotein (G) gene of the highly neuroinvasive and neurotropic strains SHBRV-18, CVS-N2c, and CVS-B2c was introduced into the non-neuroinvasive and less neurotropic SN-10 strain to provide further insight into the role of G in the pathogenesis of rabies. Phenotypic analyses of the recombinant viruses revealed, as expected, that the neurotropism of a particular rabies virus strain was a function of its G. Nevertheless, the pathogenicity of the recombinant viruses was, in every case, markedly lower than that of the wild-type viruses suggesting that while the G dictates neurotropism, other viral attributes are also important in pathogenesis. The low pathogenicity of the recombinant viruses is at least in part due to a strong increase in transcription activity. On the other hand, the production of infectious virus by the R-SHB18 recombinant virus-infected cells was significantly delayed by comparison with SHBRV-18 wild-type virus infected-cells. Replacement of the R-SHB18 G cytoplasmic domain, transmembrane domain, and stem region with its SN-10 G counterparts neither results in a significant increase in budding efficiency nor an increase in pathogenicity. These results suggest that an optimal match of the cytoplasmic domain of G with the matrix protein may not be sufficient for maximal virus budding efficiency, which is evidently a major factor of virus pathogenicity. Our studies indicate that to maintain pathogenicity, the interactions between various structural elements of rabies virus must be highly conserved and the expression of viral proteins, in particular the G protein, must be strictly controlled.
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: K
authors.initials: K
authors.lastname: Morimoto
authors.forename: H D
authors.initials: HD
authors.lastname: Foley
authors.forename: J P
authors.initials: JP
authors.lastname: McGettigan
authors.forename: M J
authors.initials: MJ
authors.lastname: Schnell
authors.forename: B
authors.initials: B
authors.lastname: Dietzschold
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral; D006224:Cricetinae; D015967:Gene Expression Regulation, Viral; D005821:Genetic Techniques; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics*; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000821:virology; D010641:Phenotype; D010957:Plasmids; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D011818:Rabies / Q000517:prevention & control / Q000821:virology*; D011819:Rabies Vaccines; D011820:Rabies virus / Q000235:genetics* / Q000472:pathogenicity*; D014158:Transcription, Genetic / Q000235:genetics; D014407:Tumor Cells, Cultured; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics*; D014774:Virulence
chemical_list: D000956:Antigens, Viral; D006023:Glycoproteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D012367:RNA, Viral; D011819:Rabies Vaccines; D014759:Viral Envelope Proteins; C064951:glycoprotein G, Rabies virus