scholarly journals The Host Response to West Nile Virus Infection Limits Viral Spread through the Activation of the Interferon Regulatory Factor 3 Pathway

2004 ◽  
Vol 78 (14) ◽  
pp. 7737-7747 ◽  
Author(s):  
Brenda L. Fredericksen ◽  
Maria Smith ◽  
Michael G. Katze ◽  
Pei-Yong Shi ◽  
Michael Gale
Keyword(s):  
West Nile Virus ◽  
Virus Replication ◽  
Host Response ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
West Nile Virus Infection ◽  
Null Mouse ◽  
Regulatory Factor ◽  
West Nile ◽  
Viral Spread

ABSTRACT Recent outbreaks of West Nile Virus (WNV) have been associated with an increase in morbidity and mortality in humans, birds, and many other species. We have initiated studies to define the molecular mechanisms by which a recent pathogenic isolate of WNV evades the host cell innate antiviral response. Biochemical and microarray analyses demonstrated that WNV induced the expression of beta interferon (IFN-β) and several IFN-stimulated genes late in infection of cultured human cells. The late expression of these antiviral genes was due to the delayed activation of the transcription factor IFN regulatory factor 3 (IRF-3). Despite this host response, WNV was still able to replicate efficiently. The effect of the IRF-3 pathway on WNV replication was assessed by examining virus replication and spread in cultures of wild-type or IRF-3-null mouse embryo fibroblasts. The absence of IRF-3 was marked by a significant increase in plaque size and a sustained production of infectious particles. Although the activation of the IRF-3 pathway was not sufficient to block virus replication, our results suggest that IRF-3 target genes function to constrain WNV infection and limit cell-to-cell virus spread.

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

2006 ◽  
Vol 80 (6) ◽  
pp. 2913-2923 ◽  
Author(s):  
Brenda L. Fredericksen ◽  
Michael Gale
Keyword(s):  
West Nile Virus ◽  
Host Response ◽  
Virus Production ◽  
Interferon Regulatory Factor ◽  
Antiviral Response ◽  
Productive Infection ◽  
Null Mouse ◽  
Regulatory Factor ◽  
West Nile ◽  
Interferon Regulatory Factor 3

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.

scholarly journals Interferon Regulatory Factor 5-Dependent Immune Responses in the Draining Lymph Node Protect against West Nile Virus Infection

2014 ◽  
Vol 88 (19) ◽  
pp. 11007-11021 ◽  
Author(s):  
L. B. Thackray ◽  
B. Shrestha ◽  
J. M. Richner ◽  
J. J. Miner ◽  
A. K. Pinto ◽  
...  
Keyword(s):  
Lymph Node ◽  
West Nile Virus ◽  
Virus Infection ◽  
Immune Responses ◽  
West Nile Virus Infection ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
West Nile ◽  
Interferon Regulatory Factor 5 ◽  
Draining Lymph Node

scholarly journals Differential Expression of Interferon (IFN) Regulatory Factors and IFN-Stimulated Genes at Early Times after West Nile Virus Infection of Mouse Embryo Fibroblasts

2007 ◽  
Vol 81 (21) ◽  
pp. 12005-12018 ◽  
Author(s):  
Svetlana V. Scherbik ◽  
Bronislava M. Stockman ◽  
Margo A. Brinton
Keyword(s):  
West Nile Virus ◽  
Mouse Embryo ◽  
Stress Responses ◽  
Host Response ◽  
West Nile Virus Infection ◽  
West Nile ◽  
Protein Levels ◽  
Mouse Embryo Fibroblasts ◽  
Primary Mouse ◽  
Embryo Fibroblasts

ABSTRACT Although lineage I West Nile virus (WNV) strain Eg101 induced beta interferon (IFN-β) production as early as 12 h after infection in primary mouse embryo fibroblasts and did not inhibit the JAK-STAT signaling pathway, it was still able to replicate efficiently. To gain insights about possible viral countermeasures used by this virus to suppress the host response, the cell transcriptional profile and the kinetics of IFN regulatory factor (IRF) expression and activation were examined at early times after infection. By 12 h after WNV infection, the majority of the up-regulated genes were ones involved in IFN pathways. However, comparison of IFN-stimulated gene (ISG) expression levels in mock-infected, IFN-treated, and virus-infected cells indicated that WNV infection suppressed the up-regulation of a subset of ISGs, including genes involved in transcriptional regulation, apoptosis, and stress responses, prior to 24 h after infection. Analysis of mRNA and protein levels for representative genes indicated that suppression was at the transcriptional and posttranscriptional levels. Translocation of IRF-3 to the nucleus was observed beginning at 8 h, IRF-7 expression was detected by 12 h, but IRF-1 expression was not detected until 24 h after infection. Virus-induced gene suppression was sufficient to overcome the effect of exogenous IFN pretreatment for 1 h but not for 4 h prior to infection. These data indicate that WNV can selectively counteract the host response at early times after infection by previously unreported mechanisms.

scholarly journals Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection

2018 ◽  
Vol 128 (11) ◽  
pp. 4980-4991 ◽  
Author(s):  
Huanle Luo ◽  
Evandro R. Winkelmann ◽  
Shuang Zhu ◽  
Wenjuan Ru ◽  
Elizabeth Mays ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Virus Infection ◽  
Virus Replication ◽  
West Nile Virus Infection ◽  
West Nile
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