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Local Type I IFN Receptor Signaling Protects against Virus Spread within the Central Nervous System¹

Claudia N. Detje^*,||, Thomas Meyer, Hauke Schmidt, Dorothea Kreuz^*, John K. Rose, Ingo Bechmann^¶, Marco Prinz and Ulrich Kalinke^2,*,||

^* Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany; Department of Cardiology, Philipps-University, Marburg, Germany; Department of Neuropathology, University of Freiburg, Freiburg, Germany; Department of Pathology, Yale University School of Medicine, New Haven CT 06510; ^¶ Dr. Senckenbergische Anatomie, Institute of Clinical Neuroanatomy, Johann Wolfgang Goethe-University, Frankfurt, Germany; and ^|| TWINCORE, Centre of Experimental and Clinical Infection Research, founded by the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany

Several neurotropic viruses such as vesicular stomatitis virus (VSV) induce peripheral neutralizing Ab responses and still can infect cells within the CNS. To address whether local type I IFN receptor (IFNAR) triggering plays a role in controlling virus replication within the brain, we generated mice with a cell type-specific IFNAR deletion in neuroectodermal cells of the CNS (NesCre^+/–IFNAR^flox/flox). Intranasal VSV infection with 10³ PFU was well tolerated by wild-type mice, whereas conventional IFNAR^–/– mice died within 2–3 days. In contrast, brain-specific NesCre^+/–IFNAR^flox/flox mice survived until day 5–6 and then became hemiplegic and died. Terminally ill NesCre^+/–IFNAR^flox/flox mice showed 10- to 100-fold higher virus loads in the brain than IFNAR^–/– mice, whereas little or no virus was found in other organs. In wild-type animals, virus could be reisolated only from the olfactory bulb until day 6 where also STAT1 activation as a measure of IFNAR triggering was detected. Virus infection was found exclusively in glomerular structures of the olfactory bulb, whereas surrounding cells that showed STAT1 phosphorylation as a measure of IFNAR trigging were free of virus. Our data indicate that upon intranasal VSV instillation, early and localized IFNAR triggering in the glomerular layer of the olfactory bulb is critically required to prevent viral spread over the entire CNS and thus confers survival.

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 study was supported by the German Research Council (Grants SFB432, B15, and ME 1648/2-1), the Volkswagen Foundation, and the Vereinigung von Freunden und Förderern der Johann Wolfgang Goethe-Universität Frankfurt am Main.

² Address correspondence and reprint requests to Dr. Ulrich Kalinke, TWINCORE, Centre of Experimental and Clinical Infection Research, Feodor-Lynen-Strasse 7, 30625 Hannover, Germany. E-mail address: ulrich.kalinke{at}twincore.de

³ Abbreviations used in this paper: VSV, vesicular stomatitis virus; IFNAR, type I IFN receptor; p.i., postinfection; i.n., intranasal; WT, wild type; eGFP, enhanced GFP; BBB, blood-brain barrier; RIG-I, retinoic acid-inducible gene I.