title: Interferon regulatory factor-1 protects from fatal neurotropic infection with vesicular stomatitis virus by specific inhibition of viral replication in neurons.
abstract: The innate immune system protects cells against invading viral pathogens by the auto- and paracrine action of type I interferon (IFN). In addition, the interferon regulatory factor (IRF)-1 can induce alternative intrinsic antiviral responses. Although both, type I IFN and IRF-1 mediate their antiviral action by inducing overlapping subsets of IFN stimulated genes, the functional role of this alternative antiviral action of IRF-1 in context of viral infections in vivo remains unknown. Here, we report that IRF-1 is essential to counteract the neuropathology of vesicular stomatitis virus (VSV). IFN- and IRF-1-dependent antiviral responses act sequentially to create a layered antiviral protection program against VSV infections. Upon intranasal infection, VSV is cleared in the presence or absence of IRF-1 in peripheral organs, but IRF-1-/- mice continue to propagate the virus in the brain and succumb. Although rapid IFN induction leads to a decline in VSV titers early on, viral replication is re-enforced in the brains of IRF-1-/- mice. While IFN provides short-term protection, IRF-1 is induced with delayed kinetics and controls viral replication at later stages of infection. IRF-1 has no influence on viral entry but inhibits viral replication in neurons and viral spread through the CNS, which leads to fatal inflammatory responses in the CNS. These data support a temporal, non-redundant antiviral function of type I IFN and IRF-1, the latter playing a crucial role in late time points of VSV infection in the brain.
authors.affiliation: Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Nair
authors.affiliation: Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Michaelsen-Preusse
authors.affiliation: Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Finsterbusch
authors.affiliation: Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Stegemann-Koniszewski
authors.affiliation: Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany; Infection Immunology Group, Department of Medical Microbiology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Dunja
authors.initials: D
authors.lastname: Bruder
authors.affiliation: Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Grashoff
authors.affiliation: Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany; Research Group Neuroinflammation and Neurodegeneration, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Korte
authors.affiliation: Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Köster
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.affiliation: Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Hauser
authors.affiliation: Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kröger
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D050856:Interferon Regulatory Factor-1 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000821:virology*; D060888:Real-Time Polymerase Chain Reaction; D054243:Vesicular Stomatitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018116:Vesiculovirus / Q000502:physiology; D014779:Virus Replication / Q000502:physiology*
chemical_list: D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse