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Journal of Virology, June 2007, p. 5940-5948, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02137-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Downregulation of an Astrocyte-Derived Inflammatory Protein, S100B, Reduces Vascular Inflammatory Responses in Brains Persistently Infected with Borna Disease Virus

Naohiro Ohtaki,¹ Wataru Kamitani,^1, Yohei Watanabe,¹ Yohei Hayashi,¹ Hideyuki Yanai,¹ Kazuyoshi Ikuta,¹ and Keizo Tomonaga^1,2*

Department of Virology, Research Institute for Microbial Diseases (BIKEN), Osaka University, Suita, Osaka 565-0871, Japan,¹ PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan²

Received 29 September 2006/ Accepted 16 March 2007

Borna disease virus (BDV) is a neurotropic virus that causes a persistent infection in the central nervous system (CNS) of many vertebrate species. Although a severe reactive gliosis is observed in experimentally BDV-infected rat brains, little is known about the glial reactions contributing to the viral persistence and immune modulation in the CNS. In this regard, we examined the expression of an astrocyte-derived factor, S100B, in the brains of Lewis rats persistently infected with BDV. S100B is a Ca²⁺-binding protein produced mainly by astrocytes. A prominent role of this protein appears to be the promotion of vascular inflammatory responses through interaction with the receptor for advanced glycation end products (RAGE). Here we show that the expression of S100B is significantly reduced in BDV-infected brains despite severe astrocytosis with increased glial fibrillary acidic protein immunoreactivity. Interestingly, no upregulation of the expression of S100B, or RAGE, was observed in the persistently infected brains even when incited with several inflammatory stimuli, including lipopolysaccharide. In addition, expression of the vascular cell adhesion molecule 1 (VCAM-1), as well as the infiltration of encephalitogenic T cells, was significantly reduced in persistently infected brains in which an experimental autoimmune encephalomyelitis was induced by immunization with myelin-basic protein. Furthermore, we demonstrated that the continuous activation of S100B in the brain may be necessary for the progression of vascular immune responses in neonatally infected rat brains. Our results suggested that BDV infection may impair astrocyte functions via a downregulation of S100B expression, leading to the maintenance of a persistent infection.

Published ahead of print on 21 March 2007.

Present address: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, 301 University Blvd., MRB 4.162, Galveston, TX 77555-1019.