title: Involvement of the rabies virus phosphoprotein gene in neuroinvasiveness.
abstract: Rabies virus (RABV), which is transmitted via a bite wound caused by a rabid animal, infects peripheral nerves and then spreads to the central nervous system (CNS) before causing severe neurological symptoms and death in the infected individual. Despite the importance of this ability of the virus to spread from a peripheral site to the CNS (neuroinvasiveness) in the pathogenesis of rabies, little is known about the mechanism underlying the neuroinvasiveness of RABV. In this study, to obtain insights into the mechanism, we conducted comparative analysis of two fixed RABV strains, Nishigahara and the derivative strain Ni-CE, which cause lethal and asymptomatic infections, respectively, in mice after intramuscular inoculation. Examination of a series of chimeric viruses harboring the respective genes from Nishigahara in the genetic background of Ni-CE revealed that the Nishigahara phosphoprotein (P) gene plays a major role in the neuroinvasiveness by mediating infection of peripheral nerves. The results obtained from both in vivo and in vitro experiments strongly suggested that the Nishigahara P gene, but not the Ni-CE P gene, is important for stable viral replication in muscle cells. Further investigation based on the previous finding that RABV phosphoprotein counteracts the host interferon (IFN) system demonstrated that the Nishigahara P gene, but not the Ni-CE P gene, functions to suppress expression of the beta interferon (IFN-β) gene (Ifn-β) and IFN-stimulated genes in muscle cells. In conclusion, we provide the first data strongly suggesting that RABV phosphoprotein assists viral replication in muscle cells by counteracting the host IFN system and, consequently, enhances infection of peripheral nerves.
authors.affiliation: The United Graduate School of Veterinary Sciences.
authors.forename: Satoko
authors.initials: S
authors.lastname: Yamaoka
authors.forename: Naoto
authors.initials: N
authors.lastname: Ito
authors.forename: Seii
authors.initials: S
authors.lastname: Ohka
authors.forename: Shohei
authors.initials: S
authors.lastname: Kaneda
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Agari
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Masatani
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Kazuma
authors.initials: K
authors.lastname: Okada
authors.forename: Kota
authors.initials: K
authors.lastname: Okadera
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Mitake
authors.forename: Teruo
authors.initials: T
authors.lastname: Fujii
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugiyama
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D007372:Interferons / Q000494:pharmacology; D051379:Mice; D018832:Molecular Chaperones; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology / Q000821:virology; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011818:Rabies / Q000235:genetics / Q000473:pathology / Q000821:virology*; D011820:Rabies virus / Q000235:genetics / Q000472:pathogenicity*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000473:pathology / Q000821:virology; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D014779:Virus Replication
chemical_list: D050856:Interferon Regulatory Factor-1; D018832:Molecular Chaperones; D064547:Myxovirus Resistance Proteins; C103961:P phosphoprotein, Rabies virus; D010750:Phosphoproteins; D012333:RNA, Messenger; D015678:Viral Structural Proteins; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase
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