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* Viral Neuroimmunology, Institut Pasteur, Paris, and
Centre d'Immunologie de Marseille-Luminy, Marseille, France;
Department of Neurology, Julius-Maximilians-University of Wuerzburg, Wuerzburg, Germany;
Instituto de Virologia, Universitad El Bosque, Bogota, Colombia;
¶ Department of Dermatology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21201; and
|| Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
Rabies virus is the etiological agent of an acute encephalitis, which in absence of post exposure treatment is fatal in almost all cases. Virus lethality rests on its ability to evade the immune response. In this study, we analyzed the role of the immuno-inhibitory molecule B7-H1 in this virus strategy. We showed that in the brain and spinal cord of mice, rabies virus infection resulted in significant up-regulation of B7-H1 expression, which is specifically expressed in infected neurons. Correlatively, clinical rabies in B7-H1–/– mice is markedly less severe than in wild-type mice. B7-H1–/– mice display resistance to rabies. Virus invasion is reduced and the level of migratory CD8 T cells increases into the nervous system, while CD4/CD8 ratio remains unchanged in the periphery. In vivo, neuronal B7-H1 expression is critically depending on TLR3 signaling and IFN-β, because TLR3–/– mice—in which IFN-β production is reduced—showed only a limited increase of B7-H1 transcripts after infection. These data provide evidence that neurons can express the B7-H1 molecule after viral stress or exposure to a particular cytokine environment. They show that the B7-H1/PD-1 pathway can be exploited locally and in an organ specific manner—here the nervous system—by a neurotropic virus to promote successful host invasion.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Institut Pasteur including PTR 186 (to M.L.), the Deutsche Forschungsgemeinschaft (SFB581, TPA8 to H.W.), and the Interdisciplinary Center for Clinical research (48-0-0, to H.W.).
2 Address correspondence and reprint requests to Dr. Monique Lafon, Unité de Neuroimmunologie Virale, Institut Pasteur, 25, rue du Dr. Roux, 75724 Paris Cedex 15, France. E-mail address: mlafon{at}pasteur.fr
3 Abbreviations used in this paper: RABV, Rabies virus; NS, nervous system; Rt, room terperature; WT, wild type.
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