Interferon Regulatory Factor-1 Protects from Fatal Neurotropic Infection with Vesicular Stomatitis Virus by Specific Inhibition of Viral Replication in Neurons

PLoS Pathogens

Mario Köster¹  Kristin Michaelsen-Preusse¹  Hansjörg Hauser²  Sabine Stegemann-Koniszewski³  Dunja Bruder³  Martina Grashoff⁴  Andrea Kröger⁵  Katja Finsterbusch⁶  Sharmila Nair⁶  Martin Korte⁶  Ulrich Kalinke⁷ 

[1] Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany;Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany;Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany;Infection Immunology Group, Department of Medical Microbiology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany;Institute for Experimental Infection Research, TWINCORE, Hannover, Germany;Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany;Research Group Neuroinflammation and Neurodegeneration, Helmholtz Centre for Infection Research, Braunschweig, Germany

关键词: Vesicular stomatitis virus;    Viral replication;    Interferons;    Cerebrum;    T cells;    Immune response;    Neurons;    Brainstem;   

DOI  :  10.1371/journal.ppat.1003999

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY