New insights into innate immune restriction of West Nile virus infection

Abstract

West Nile virus (WNV) is an encephalitic flavivirus that has provided a valuable experimental system for studying viral pathogenesis and immunity. Although in vitro approaches and mouse models of infection have identified pattern recognition receptor and interferon pathways that control WNV infection, our appreciation of specific antiviral effectors has been more limited. In this review, we highlight recent advances in our understanding of the host factors that restrict WNV infection in mammals and insects, especially those resulting from large-scale screening approaches.

Figure 1. The IFN-mediated antiviral response to WNV

WNV infection is sensed by pattern-recognition receptors (PRRs) including RIG-I-like receptors (RIG-I, MDA5) and Toll-like receptors (TLR3, TLR7). These signal to activate IRF-family transcription factors, which induce IFN-β transcription and production. New evidence suggests that a DNA sensor, cGAS, also activates the antiviral response after WNV infection. IFN-α/β signals in an autocrine and paracrine manner to induce the expression of hundreds of IFN-stimulated genes (ISGs) that inhibit viral replication by a variety of mechanisms. Many ISGs have been shown to restrict WNV replication in vitro (a selection of which are listed), but few of these have confirmed roles in controlling WNV pathogenesis in vivo (e.g., PKR, IFIT2, viperin, and RNase L). Virulent strains of WNV evade the antiviral activity of IFIT1; only mutant viruses that lack 2′-O methylation on the 5′ cap structure of their viral RNA are restricted by IFIT1.

Figure 2. Limitations of genetic screens to identify antiviral interferon-stimulated genes (ISGs)

Large-scale ectopic expression and gene silencing screens have provided new insights into the IFN-induced host factors that restrict infection by WNV and other viruses in vitro. However, the roles of these host factors in controlling WNV pathogenesis in vivo remain less clear, owing to several limitations of this approach. First, viral infection triggers global changes in cellular gene expression and produces an antiviral milieu that is absent in the context of ectopic expression of a single ISG. Second, the antiviral response in transformed or knockout cell lines used for genetic screens may not faithfully represent that found in differentiated and immune competent cells. Third, some restriction factors may remain undetected because their antiviral activities are antagonized by the virulent strain of virus used in the genetic screen.