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

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. © 2014 nair et al.