Interferon regulatory factor-1 protects from fatal neurotropic infection with vesicular stomatitis virus by specific inhibition of viral replication in neurons

• Published in: PLoS pathogens Vol. 10; no. 3; p. e1003999
• Main Authors: Nair, Sharmila, Michaelsen-Preusse, Kristin, Finsterbusch, Katja, Stegemann-Koniszewski, Sabine, Bruder, Dunja, Grashoff, Martina, Korte, Martin, Köster, Mario, Kalinke, Ulrich, Hauser, Hansjörg, Kröger, Andrea
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-03-2014; Public Library of Science (PLoS)
• Subjects: Animals; Brain research; Enzyme-Linked Immunosorbent Assay; Experiments; Fluorescent Antibody Technique; Genetic aspects; Genetic research; Health aspects; Immune system; Immunohistochemistry; Infections; Influenza; Interferon; Interferon Regulatory Factor-1 - immunology; Interferon Regulatory Factor-1 - metabolism; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurological research; Neurons; Neurons - virology; Real-Time Polymerase Chain Reaction; Survival analysis; Transcription factors; Vesicular Stomatitis - immunology; Vesicular Stomatitis - metabolism; Vesicular Stomatitis - pathology; Vesiculovirus - physiology; Viral infections; Virus Replication - physiology; Viruses; Germany; Immunohistochemistry; Enzyme-Linked Immunosorbent Assay; Neurons; Mice, Inbred C57BL; Mice, Knockout; Vesiculovirus; Animals; Interferon Regulatory Factor-1; Virus Replication; Fluorescent Antibody Technique; Vesicular Stomatitis; Mice; Real-Time Polymerase Chain Reaction
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003999

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.