The innate immune playbook for restricting West Nile virus infection

Abstract

West Nile virus (WNV) is an emerging mosquito-borne flavivirus that causes annual epidemics of encephalitic disease throughout the world. Despite the ongoing risk to public health, no approved vaccines or therapies exist for use in humans to prevent or combat WNV infection. The innate immune response is critical for controlling WNV replication, limiting virus-induced pathology, and programming protective humoral and cell-mediated immunity to WNV infection. The RIG-I like receptors, Toll-like receptors, and Nod-like receptors detect and respond to WNV by inducing a potent antiviral defense program, characterized by production of type I IFN, IL-1β and expression of antiviral effector genes. Recent research efforts have focused on uncovering the mechanisms of innate immune sensing, antiviral effector genes that inhibit WNV, and countermeasures employed by WNV to antagonize innate immune cellular defenses. In this review, we highlight the major research findings pertaining to innate immune regulation of WNV infection.

Figure 1

Innate immune signaling. (A) Following non-self RNA binding, RIG-I and MDA5 interact with MAVS to induce the expression of IFN-β and IRF-3 target genes; (B) TLR3 and TLR7 bind to non-self RNA to trigger IRF-3, IRF-7, and NF-κB dependent gene expression; (C) NLPR3 interacts with ASC, leading to caspase-1 activation and IL-1β processing; (D) Secreted type I IFN leads to formation of the ISGF3 complex that translocates to the nucleus and induces expression of interferon-stimulated response element (ISRE)-dependent genes, including IRF-7, IFN-α subtypes, and ISGs. Viral proteins that antagonize these pathways are indicated.