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.

Author Summary

IRFs are a family of transcription factors that play a key role in viral defense. Apart from their function in the adaptive immune system, recent work revealed that several IRFs contribute to antiviral response independent of secreted IFN. IRFs have been developed earlier in evolution than IFN and are regarded as precursor of today's IFN system, acting only on an intrinsic level. IRF-1 by itself exhibits antiviral effects that are exerted by the induction of a set of genes that overlaps the set of IFN-induced genes (ISGs). Our data show that IRF-1 contributes decisively for the protection of mice from neurotropic Vesicular stomatitis virus (VSV), a virus similar to rabies virus. Mice, deficient in IRF-1, are highly vulnerable to VSV infection and succumb with signs of encephalitis. Although type I IFN action is a prerequisite for survival from the infection, IRF-1 becomes increasingly crucial in neuronal tissue at a time point where clearance of the virus has not been achieved. The data highlight the importance of IRF-1 as an antiviral agent that acts in combination with the IFN system.