title: Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon Beta producers that protect from lethal encephalitis.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the H annover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Claudia N
authors.initials: CN
authors.lastname: Detje
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the H annover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Chintan
authors.initials: C
authors.lastname: Chhatbar
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the H annover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Spanier
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Chittappen K
authors.initials: CK
authors.lastname: Prajeeth
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the H annover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Soldner
authors.affiliation: Laboratory of Biotechnology Applied Pharmacology, École Normale Supérieure de Cachan, Cachan Cedex, France.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Tovey
authors.affiliation: Institute for Medical Microbiology and Hospital Hygiene, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany Organ-Specific Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schlüter
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stangel
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the H annover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany ulrich.kalinke@twincore.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000821:virology; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000276:immunology*; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D016899:Interferon-beta / Q000172:deficiency / Q000378:metabolism*; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000276:immunology / Q000821:virology; D009830:Olfactory Bulb / Q000276:immunology* / Q000821:virology; D018353:Rhabdoviridae Infections / Q000276:immunology*; D016019:Survival Analysis; D018116:Vesiculovirus / Q000276:immunology*
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D016899:Interferon-beta; D008156:Luciferases