Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon Beta producers that protect from lethal encephalitis

Previously we found that following intranasal (i.n.) infection with neurotropic vesicular stomatitis virus (VSV) type I interferon receptor (IFNAR) triggering of neuroectodermal cells was critically required to constrain intracerebral virus spread. To address whether locally active IFN-β was induced...

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Bibliographic Details
Published in:Journal of virology 2015-03, Vol.89 (5), p.2731-2738
Main Authors: Detje, Claudia N, Lienenklaus, Stefan, Chhatbar, Chintan, Spanier, Julia, Prajeeth, Chittappen K, Soldner, Claudia, Tovey, Michael G, Schlüter, Dirk, Weiss, Siegfried, Stangel, Martin, Kalinke, Ulrich
Format: Article
Language:English
Subjects:
Animals
Astrocytes - immunology
Astrocytes - virology
Disease Models, Animal
Encephalitis, Viral - immunology
Gene Expression Profiling
Genes, Reporter
Green Fluorescent Proteins - analysis
Green Fluorescent Proteins - genetics
Interferon-beta - deficiency
Interferon-beta - secretion
Luciferases - analysis
Luciferases - genetics
Mice, Inbred C57BL
Mice, Knockout
Neurons - immunology
Neurons - virology
Olfactory Bulb - immunology
Olfactory Bulb - virology
Pathogenesis and Immunity
Rhabdoviridae Infections - immunology
Survival Analysis
Vesicular stomatitis virus
Vesiculovirus - immunology
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Summary:Previously we found that following intranasal (i.n.) infection with neurotropic vesicular stomatitis virus (VSV) type I interferon receptor (IFNAR) triggering of neuroectodermal cells was critically required to constrain intracerebral virus spread. To address whether locally active IFN-β was induced proximally, we studied spatiotemporal conditions of VSV-mediated IFN-β induction. To this end, we performed infection studies with IFN-β reporter mice. One day after intravenous (i.v.) VSV infection, luciferase induction was detected in lymph nodes. Upon i.n. infection, luciferase induction was discovered at similar sites with delayed kinetics, whereas on days 3 and 4 postinfection enhanced luciferase expression additionally was detected in the foreheads of reporter mice. A detailed analysis of cell type-specific IFN-β reporter mice revealed that within the olfactory bulb IFN-β was expressed by neuroectodermal cells, primarily by astrocytes and to a lesser extent by neurons. Importantly, locally induced type I IFN triggered distal parts of the brain as indicated by the analysis of ISRE-eGFP mice which after i.n. VSV infection showed enhanced green fluorescent protein (eGFP) expression throughout the brain. Compared to wild-type mice, IFN-β(-/-) mice showed increased mortality to i.n. VSV infection, whereas upon i.v. infection no such differences were detected highlighting the biological significance of intracerebrally expressed IFN-β. In conclusion, upon i.n. VSV instillation, IFN-β responses mounted by astrocytes within the olfactory bulb critically contribute to the antiviral defense by stimulating distal IFN-β-negative brain areas and thus arresting virus spread. The central nervous system has long been considered an immune privileged site. More recently, it became evident that specialized immune mechanisms are active within the brain to control pathogens. Previously, we showed that virus, which entered the brain via the olfactory route, was arrested within the olfactory bulb by a type I IFN-dependent mechanism. Since peripheral type I IFN would not readily cross the blood-brain barrier and within the brain thus far no abundant type I IFN responses have been detected, here we addressed from where locally active IFN originated from. We found that upon intranasal VSV instillation, primarily astrocytes, and to a lesser extent neurons, were stimulated within the olfactory bulb to mount IFN-β responses that also activated and protected distal brain areas. Our res
ISSN:0022-538X
1098-5514
DOI:10.1128/JVI.02044-14