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PLoS Pathog. 2014 Mar 27;10(3):e1003999. doi: 10.1371/journal.ppat.1003999. eCollection 2014 Mar.

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

Author information

1
Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
2
Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany.
3
Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
4
Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany; Infection Immunology Group, Department of Medical Microbiology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
5
Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany; Research Group Neuroinflammation and Neurodegeneration, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6
Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
7
Institute for Experimental Infection Research, TWINCORE, Hannover, Germany.

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.

PMID:
24675692
PMCID:
PMC3968136
DOI:
10.1371/journal.ppat.1003999
[Indexed for MEDLINE]
Free PMC Article

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