Upon Intranasal Vesicular Stomatitis Virus Infection, Astrocytes in the Olfactory Bulb Are Important Interferon Beta Producers That Protect from Lethal Encephalitis
| Autor: | Chittappen K. Prajeeth, Martin Stangel, Siegfried Weiss, Chintan Chhatbar, Dirk Schlüter, Julia Spanier, Stefan Lienenklaus, Claudia Soldner, Ulrich Kalinke, Claudia N. Detje, Michael G. Tovey |
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| Přispěvatelé: | Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany. |
| Rok vydání: | 2015 |
| Předmět: |
Green Fluorescent Proteins
Immunology Central nervous system Biology Microbiology Virus Green fluorescent protein Immune system Genes Reporter Rhabdoviridae Infections Virology medicine Animals Luciferase Encephalitis Viral Luciferases Mice Knockout Neurons Gene Expression Profiling Interferon-beta Vesiculovirus biology.organism_classification medicine.disease Olfactory Bulb Survival Analysis Olfactory bulb Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Vesicular stomatitis virus Astrocytes Insect Science Pathogenesis and Immunity Encephalitis |
| Zdroj: | Journal of Virology. 89:2731-2738 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.02044-14 |
| Popis: | 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. IMPORTANCE 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 results are surprising because in other infection models astrocytes have not yet been identified as major type I IFN producers. |
| Databáze: | OpenAIRE |
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