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Journal of Virology, March 2005, p. 3448-3458, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3448-3458.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Nuclear Localization of Japanese Encephalitis Virus Core Protein Enhances Viral Replication{dagger}

Yoshio Mori,1 Tamaki Okabayashi,1 Tetsuo Yamashita,1 Zijiang Zhao,2 Takaji Wakita,2 Kotaro Yasui,2 Futoshi Hasebe,3 Masayuki Tadano,4 Eiji Konishi,5 Kohji Moriishi,1 and Yoshiharu Matsuura1*

Research Center for Emerging Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Osaka,1 Department of Microbiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo,2 Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki,3 Division of Molecular Virology and Oncology, University of the Ryukyu, Okinawa,4 Department of Health Sciences, Kobe University School of Medicine, Hyogo, Japan5

Received 13 September 2004/ Accepted 3 November 2004

Japanese encephalitis virus (JEV) core protein was detected in both the nucleoli and cytoplasm of mammalian and insect cell lines infected with JEV or transfected with the expression plasmid of the core protein. Mutation analysis revealed that Gly42 and Pro43 in the core protein are essential for the nuclear and nucleolar localization. A mutant M4243 virus in which both Gly42 and Pro43 were replaced by Ala was recovered by plasmid-based reverse genetics. In C6/36 mosquito cells, the M4243 virus exhibited RNA replication and protein synthesis comparable to wild-type JEV, whereas propagation in Vero cells was impaired. The mutant core protein was detected in the cytoplasm but not in the nucleus of either C6/36 or Vero cell lines infected with the M4243 virus. The impaired propagation of M4243 in mammalian cells was recovered by the expression of wild-type core protein in trans but not by that of the mutant core protein. Although M4243 mutant virus exhibited a high level of neurovirulence comparable to wild-type JEV in spite of the approximately 100-fold-lower viral propagation after intracerebral inoculation to 3-week-old mice of strain Jcl:ICR, no virus was recovered from the brain after intraperitoneal inoculation of the mutant. These results indicate that nuclear localization of JEV core protein plays crucial roles not only in the replication in mammalian cells in vitro but also in the pathogenesis of encephalitis induced by JEV in vivo.

* Corresponding author. Mailing address: Research Center for Emerging Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-8340. Fax: 81-6-6879-8269. E-mail: matsuura{at}biken.osaka-u.ac.jp.

{dagger} This study is dedicated to the memory of Ikuko Yanase.

Journal of Virology, March 2005, p. 3448-3458, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3448-3458.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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