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Journal of Virology, November 2005, p. 13509-13518, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13509-13518.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

Jürgen Hausmann,1* Axel Pagenstecher,2 Karen Baur,1 Kirsten Richter,1 Hanns-Joachim Rziha,3 and Peter Staeheli1*

Department of Virology,1 Department of Neuropathology, University of Freiburg, D-79104 Freiburg, Germany,2 Friedrich-Loeffler-Institutes, Institute of Immunology, D-72076 Tuebingen, Germany3

Received 30 June 2005/ Accepted 1 August 2005

Borna disease virus (BDV) frequently causes meningoencephalitis and fatal neurological disease in young but not old mice of strain MRL. Disease does not result from the virus-induced destruction of infected neurons. Rather, it is mediated by H-2k-restricted antiviral CD8 T cells that recognize a peptide derived from the BDV nucleoprotein N. Persistent BDV infection in mice is not spontaneously cleared. We report here that N-specific vaccination can protect wild-type MRL mice but not mutant MRL mice lacking gamma interferon (IFN-{gamma}) from persistent infection with BDV. Furthermore, we observed a significant degree of resistance of old MRL mice to persistent BDV infection that depended on the presence of CD8 T cells. We found that virus initially infected hippocampal neurons around 2 weeks after intracerebral infection but was eventually cleared in most wild-type MRL mice. Unexpectedly, young as well as old IFN-{gamma}-deficient MRL mice were completely susceptible to infection with BDV. Moreover, neurons in the CA1 region of the hippocampus were severely damaged in most diseased IFN-{gamma}-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-{gamma}-deficient mice but not in those of wild-type mice, presumably because of increased intracerebral synthesis of interleukin-13 and the chemokines CCL1 and CCL11, which can attract eosinophils. These results demonstrate that IFN-{gamma} plays a central role in host resistance against infection of the central nervous system with BDV and in clearance of BDV from neurons. They further indicate that IFN-{gamma} may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

* Corresponding author. Present address for Jürgen Hausmann: Bavarian Nordic GmbH, Fraunhoferstrasse 13, D-82152 Martinsried, Germany. Phone: 49-89-8565-1329. Fax: 49-89-8565-1356. E-mail: juergen.hausmann{at}bavarian-nordic.com. Mailing address for Peter Staeheli: Department of Virology, University of Freiburg, Hermann- Herder-Strasse 11, D-79104 Freiburg, Germany. Phone: 49-761-203-6579. Fax: 49-761-203-5350. E-mail: peter.staeheli{at}uniklinik-freiburg.de.

Journal of Virology, November 2005, p. 13509-13518, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13509-13518.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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