West Nile Virus Evades Activation of Interferon Regulatory Factor 3 through RIG-I-Dependent and -Independent Pathways without Antagonizing Host Defense Signaling

Abstract

The ability of viruses to control and/or evade the host antiviral response is critical to the establishment of a productive infection. We have previously shown that West Nile virus NY (WNV-NY) delays activation of interferon regulatory factor 3 (IRF-3), a transcription factor critical to the initiation of the antiviral response. Here we demonstrate that the delayed activation of IRF-3 is essential for WNV-NY to achieve maximum virus production. Furthermore, WNV-NY utilizes a unique mechanism to control activation of IRF-3. In contrast to many other viruses that impose a nonspecific block to the IRF-3 pathway, WNV-NY eludes detection by the host cell at early times postinfection. To better understand this process, we assessed the role of the pathogen recognition receptor (PRR) retinoic acid-inducible gene I (RIG-I) in sensing WNV-NY infection. RIG-I null mouse embryo fibroblasts (MEFs) retained the ability to respond to WNV-NY infection; however, the onset of the host response was delayed compared to wild-type (WT) MEFs. This suggests that RIG-I is involved in initially sensing WNV-NY infection, while other PRRs sustain and/or amplify the host response later in infection. The delayed initiation of the host response correlated with an increase in WNV-NY replication in RIG-I null MEFs compared to WT MEFs. Our data suggest that activation of the host response by RIG-I early in infection is important for controlling replication of WNV-NY. Furthermore, pathogenic strains of WNV may have evolved to circumvent stimulation of the host response until after replication is well under way.

miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates

“…irf7 is a member of the irf family, and irf members often function in host defense and inflammation [27][28][29][30]. An inflammation pathway might be involved in HSC and myeloid lineage differentiation in zebrafish [31,32].…”

Inflammasomes and its importance in viral infections

“…The C-terminal regulatory domain binds with dsRNA resulting in conformational changes that lead to its oligomerisation and the subsequent interaction of RIG-1 with MAVS through a CARD-CARD interaction [80,83]. The role of RIG-1 in the production of type 1 IFNs has been demonstrated in numerous viruses including Newcastle disease virus, VSV, Sendai virus, HCV, Japanese encephalitis virus, influenza A virus, rabies virus, measles virus, and RSV [84][85][86][87][88][89][90][91]. Further, a role of RIG-1 in triggering the immune response has been demonstrated for numerous viruses including DENV serotype 2, WNV, RSV, and HCV [86,87,[92][93][94].…”

“…The role of RIG-1 in the production of type 1 IFNs has been demonstrated in numerous viruses including Newcastle disease virus, VSV, Sendai virus, HCV, Japanese encephalitis virus, influenza A virus, rabies virus, measles virus, and RSV [84][85][86][87][88][89][90][91]. Further, a role of RIG-1 in triggering the immune response has been demonstrated for numerous viruses including DENV serotype 2, WNV, RSV, and HCV [86,87,[92][93][94]. It has been demonstrated that rhabdovirus VSV infection in murine DCs induces RIG-1-dependent production of IL-1b and IL-18 via NF-jB, caspase-1, and caspase-3 activation; thus, RIG-1 is an inflammasome activator.…”

Innate immune evasion by hepatitis C virus and West Nile virus

“…Rather, WNV delays activation of PRR signaling long enough to give the virus a replicative advantage within the infected cell [44]. The delayed activation of IRF-3 during WNV infection results in a robust α/β IFN response that slows cell to cell virus spread but this response is largely ineffective at limiting infection by the emergent strain [45].…”

“…Studies using cells from gene knockout mice revealed that WNV signals innate defenses through RIG-I-dependent mechanisms as well as through processes independent of RIG-I likely involving MDA5 [44]. These studies revealed that efficient viral replication is dependent upon the virus delaying the activation of innate defenses inasmuch as ectopic activation of the RIG-I pathway results in a severe limitation of virus replication [44]. The delay in PRR detection of WNV provides the virus with a window of opportunity to essentially replicate unimpeded during the early stages of infection.…”