West Nile virus evades activation of interferon regulatory factor 3 through RIG-I-dependent and -independent pathways without antagonizing host defense signaling.
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.
Fredericksen
Brenda L
BL
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, USA.
Gale
Michael
M
D000818:Animals; D002460:Cell Line; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D010948:Viral Plaque Assay; D014779:Virus Replication; D014901:West Nile Fever / Q000276:immunology*; D014902:West Nile virus / Q000472:pathogenicity* / Q000502:physiology
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C502844:Rai1 protein, mouse; D015534:Trans-Activators