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Journal of Virology, September 2005, p. 11801-11812, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11801-11812.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Rabies Virus-Induced Activation of Mitogen-Activated Protein Kinase and NF-{kappa}B Signaling Pathways Regulates Expression of CXC and CC Chemokine Ligands in Microglia

Kazuo Nakamichi,1 Megumi Saiki,1,2 Makoto Sawada,3 Mutsuyo Takayama-Ito,1 Yutaka Yamamuro,2 Kinjiro Morimoto,1 and Ichiro Kurane1*

Department of Virology 1, National Institute of Infectious Diseases, Toyama, Shinjuku, Tokyo 162-8640,1 Department of Animal Science, College of Bioresource Sciences, Nihon University, Kameino, Fujisawa, Kanagawa 252-8510,2 Department of Brain Life Science, Research Institute for Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601, Japan3

Received 14 February 2005/ Accepted 5 May 2005

Following virus infection of the central nervous system, microglia, the ontogenetic and functional equivalents of macrophages in somatic tissues, act as sources of chemokines, thereby recruiting peripheral leukocytes into the brain parenchyma. In the present study, we have systemically examined the growth characteristics of rabies virus (RV) in microglia and the activation of cellular signaling pathways leading to chemokine expression upon RV infection. In RV-inoculated microglia, the synthesis of the viral genome and the production of virus progenies were significantly impaired, while the expression of viral proteins was observed. Transcriptional analyses of the expression profiles of chemokine genes revealed that RV infection, but not exposure to inactivated virions, strongly induces the expression of CXC chemokine ligand 10 (CXCL10) and CC chemokine ligand 5 (CCL5) in microglia. RV infection triggered the activation of signaling pathways mediated by mitogen-activated protein kinases, including p38, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase, and nuclear factor {kappa}B (NF-{kappa}B). RV-induced expression of CXCL10 and CCL5 was achieved by the activation of p38 and NF-{kappa}B pathways. In contrast, the activation of ERK1/2 was found to down-regulate CCL5 expression in RV-infected microglia, despite the fact that it was involved in partial induction of CXCL10 expression. Furthermore, NF-{kappa}B signaling upon RV infection was augmented via a p38-mediated mechanism. Taken together, these results indicate that the strong induction of CXCL10 and CCL5 expression in microglia is precisely regulated by the activation of multiple signaling pathways through the recognition of RV infection.

* Corresponding author. Mailing address: Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. Phone: 81-3-5285-1169. Fax: 81-3-5285-1169. E-mail: kurane{at}nih.go.jp.

Journal of Virology, September 2005, p. 11801-11812, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11801-11812.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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