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

Date Published: March 27, 2014

Publisher: Public Library of Science

Author(s): Sharmila Nair, Kristin Michaelsen-Preusse, Katja Finsterbusch, Sabine Stegemann-Koniszewski, Dunja Bruder, Martina Grashoff, Martin Korte, Mario Köster, Ulrich Kalinke, Hansjörg Hauser, Andrea Kröger, Volker Thiel.


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.

Partial Text

The rapid production of type I Interferon (IFN) in response to a viral attack serves as a crucial antiviral defense mechanism in mammals [1]–[3]. The type I IFN response to invading pathogens is a biphasic phenomenon. First, the detection of RNA viruses occurs through the recognition of pathogen associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs) such as the toll like receptors (TLRs) or retinoic acid inducible gene-1 (RIG-I) like receptors (RLRs) which initiate a signaling cascade to activate transcription factors like interferon regulatory factor (IRF)-3 and NF-κB to induce the type I IFNs [4]–[6]. Second, the IFNs act in an autocrine and paracrine manner to induce IFN stimulated genes (ISGs), the products of which act collectively to interfere with viral replication and spread.

The innate immune system is essential to limit viral replication before adaptive immunity is stimulated. The best characterized cytokine induced after virus enters a cell is the type I IFN, which subsequently mediates innate responses to inhibit viral propagation. In this study we report IRF-1 as an essential regulator of the host innate antiviral response that is not involved in the rapid IFN induction. Using IRF-1−/− mice with a specific IFNAR deletion in the CNS we could demonstrate a particular IRF-1-dependent antiviral response. Detailed analysis of the viral titers in different brain regions revealed a temporal role of IRF-1 in the control of viral replication. While type I IFN plays a critical role in early stages of infection, IRF-1 is essential in limiting viral replication at later stages. Overall our results show an important role of IRF-1 in mediating a well-orchestrated antiviral response during VSV infections in the brain. We propose that IRF-1 allies with the IFN mediated responses to achieve another layer of antiviral protection to tighten the innate immune response network.




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