Measure and countermeasure: type I IFN (IFN-alpha/beta) antiviral response against West Nile virus

Abstract

As a first line of defense after viral infection, host cells develop an intrinsic immune response to control virus dissemination and protect against serious infection. Recent experiments have shown a dominant role of the IFN-alpha/beta response in protection against lethal West Nile virus (WNV) by limiting the cellular and tissue tropism of infection. This review will focus on advances in identifying the host sensors that detect WNV and the adaptor molecules and signaling pathways that regulate the induction of IFN-alpha/beta defenses that limit WNV replication, spread and pathogenesis.

Fig. 1

Detection of WNV and activation of IFN-α/β genes and ISG according to the 2-step model. Infection by WNV produces dsRNA intermediates in the cytosol that are detected as non-self by the host. RIG-I acts as the main sensor for WNV during the early steps of infection. RIG-I activation promotes interaction with IPS-1 that leads to the recruitment of TRAF3, TBK1 and IKK_ε, which phosphorylate and activate IRF-3. Very small amounts of constitutively produced IRF-7 may be activated via this pathway. IRF-3 then translocates into the nucleus, binds the IFN-β gene promoter and promotes transcription and translation. Secretion of IFN-β by the infected cells results in paracrine type I IFN signaling through the IFNAR receptor. Activation of IFNAR induces phosphorylation of JAK1 and Tyk2, which can promote the formation of the heterotrimer IFN-stimulated gene factor-3 formed by STAT1, STAT2 and IRF-9. Ultimately, translocation into the nucleus of IFN-stimulated gene factor-3 induces hundreds of ISGs, including IRF-7. During late phases of infection, detection of WNV also relies on MDA5. Induction of the IFN-α and IFN-β genes then occurs mainly via the transcriptional activity of IRF-7. Detection of WNV during the late phase may also involve PKR, which induces the IFN-α and IFN-β genes via an unknown mechanism (potentially via NF- κβ activation and/or TRAF3, TBK1 and IKK_ε recruitment). In MΦ and mDC, IFN-β is induced at least partially through IPS-1-dependent yet IRF-3 and IRF-7-independent pathways. In MΦ, IRF-3 regulates the basal expression of host defense genes as described in the text. X = Sites in the recognition and signaling cascade at which WNV has developed specific mechanisms to counteract IFN. These are described in detail in the text.