Involvement of the rabies virus phosphoprotein gene in neuroinvasiveness

Satoko Yamaoka, Naoto Ito, Seii Ohka, Shohei Kaneda, Hiroko Nakamura, Takahiro Agari, Tatsunori Masatani, Keisuke Nakagawa, Kazuma Okada, Kota Okadera, Hiromichi Mitake, Teruo Fujii, Makoto Sugiyama

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12327-12338
Number of pages12
JournalJournal of virology
Volume87
Issue number22
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Yamaoka, S., Ito, N., Ohka, S., Kaneda, S., Nakamura, H., Agari, T., Masatani, T., Nakagawa, K., Okada, K., Okadera, K., Mitake, H., Fujii, T., & Sugiyama, M. (2013). Involvement of the rabies virus phosphoprotein gene in neuroinvasiveness. Journal of virology, 87(22), 12327-12338. https://doi.org/10.1128/JVI.02132-13