scholarly journals RNase L Plays a Role in the Antiviral Response to West Nile Virus

2006 ◽  
Vol 80 (6) ◽  
pp. 2987-2999 ◽  
Author(s):  
Svetlana V. Scherbik ◽  
Jayashree M. Paranjape ◽  
Bronislava M. Stockman ◽  
Robert H. Silverman ◽  
Margo A. Brinton
Keyword(s):  
West Nile Virus ◽  
Antiviral Response ◽  
Dominant Negative ◽  
Activity Levels ◽  
Rnase L ◽  
Genomic Rna ◽  
Oligoadenylate Synthetase ◽  
Susceptible Mouse ◽  
West Nile ◽  
Cellular Antiviral Response

ABSTRACT Alleles at the Flv locus determine disease outcome after a flavivirus infection in mice. Although comparable numbers of congenic resistant and susceptible mouse embryo fibroblasts (MEFs) are infected by the flavivirus West Nile virus (WNV), resistant MEFs produce ∼100- to 150-fold lower titers than susceptible ones and flavivirus titers in the brains of resistant and susceptible animals can differ by >10,000-fold. The Flv locus was previously identified as the 2′-5′ oligoadenylate synthetase 1b (Oas1b) gene. Oas gene expression is up-regulated by interferon (IFN), and after activation by double-stranded RNA, some mouse synthetases produce 2-5A, which activates latent RNase L to degrade viral and cellular RNAs. To determine whether the lower levels of intracellular flavivirus genomic RNA from resistant mice detected in cells at all times after infection were mediated by RNase L, RNase L activity levels in congenic resistant and susceptible cells were compared. Similar moderate levels of RNase L activation by transfected 2-5A were observed in both types of uninfected cells. After WNV infection, the mRNAs of IFN-β and three Oas genes were up-regulated to similar levels in both types of cells. However, significant levels of RNase L activity were not detected until 72 h after WNV infection and the patterns of viral RNA cleavage products generated were similar in both types of cells. When RNase L activity was down-regulated in resistant cells via stable expression of a dominant negative RNase L mutant, ∼5- to 10-times-higher yields of WNV were produced. Similarly, about ∼5- to 10-times-higher virus yields were produced by susceptible C57BL/6 RNase L−/− cells compared to RNase L+/+ cells that were either left untreated or pretreated with IFN and/or poly(I) · poly(C). The data indicate that WNV genomic RNA is susceptible to RNase L cleavage and that RNase L plays a role in the cellular antiviral response to flaviviruses. The results suggest that RNase L activation is not a major component of the Oas1b-mediated flavivirus resistance phenotype.

scholarly journals PKR and RNase L Contribute to Protection against Lethal West Nile Virus Infection by Controlling Early Viral Spread in the Periphery and Replication in Neurons

2006 ◽  
Vol 80 (14) ◽  
pp. 7009-7019 ◽  
Author(s):  
Melanie A. Samuel ◽  
Kevin Whitby ◽  
Brian C. Keller ◽  
Anantha Marri ◽  
Winfried Barchet ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Mortality Rate ◽  
Type I ◽  
Rnase L ◽  
Type I Ifn ◽  
Oligoadenylate Synthetase ◽  
West Nile ◽  
Peripheral Tissues ◽  
Viral Spread ◽  
Viral Burden

ABSTRACT West Nile virus (WNV) is a neurotropic, mosquito-borne flavivirus that can cause lethal meningoencephalitis. Type I interferon (IFN) plays a critical role in controlling WNV replication, spread, and tropism. In this study, we begin to examine the effector mechanisms by which type I IFN inhibits WNV infection. Mice lacking both the interferon-induced, double-stranded-RNA-activated protein kinase (PKR) and the endoribonuclease of the 2′,5′-oligoadenylate synthetase-RNase L system (PKR−/− × RL−/−) were highly susceptible to subcutaneous WNV infection, with a 90% mortality rate compared to the 30% mortality rate observed in congenic wild-type mice. PKR−/− × RL−/− mice had increased viral loads in their draining lymph nodes, sera, and spleens, which led to early viral entry into the central nervous system (CNS) and higher viral burden in neuronal tissues. Although mice lacking RNase L showed a higher CNS viral burden and an increased mortality, they were less susceptible than the PKR−/− × RL−/− mice; thus, we also infer an antiviral role for PKR in the control of WNV infection. Notably, a deficiency in both PKR and RNase L resulted in a decreased ability of type I IFN to inhibit WNV in primary macrophages and cortical neurons. In contrast, the peripheral neurons of the superior cervical ganglia of PKR−/− × RL−/− mice showed no deficiency in the IFN-mediated inhibition of WNV. Our data suggest that PKR and RNase L contribute to IFN-mediated protection in a cell-restricted manner and control WNV infection in peripheral tissues and some neuronal subtypes.

scholarly journals Activation of 2′ 5′-Oligoadenylate Synthetase by Stem Loops at the 5′-End of the West Nile Virus Genome

PLoS ONE ◽  
2014 ◽  
Vol 9 (3) ◽  
pp. e92545 ◽  
Author(s):  
Soumya Deo ◽  
Trushar R. Patel ◽  
Edis Dzananovic ◽  
Evan P. Booy ◽  
Khalid Zeid ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Virus Genome ◽  
Oligoadenylate Synthetase ◽  
The West ◽  
West Nile

scholarly journals Viral determinants in the NS3 helicase and 2K peptide that promote West Nile virus resistance to antiviral action of 2′,5′-oligoadenylate synthetase 1b

Virology ◽  
2010 ◽  
Vol 399 (1) ◽  
pp. 176-185 ◽  
Author(s):  
Eva Mertens ◽  
Anna Kajaste-Rudnitski ◽  
Shessy Torres ◽  
Anneke Funk ◽  
Marie-Pascale Frenkiel ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Virus Resistance ◽  
Antiviral Action ◽  
Oligoadenylate Synthetase ◽  
West Nile ◽  
Viral Determinants

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.

Infection of mouse neurones by West Nile virus is modulated by the interferon‐inducible 2′‐5′ oligoadenylate synthetase 1b protein

2003 ◽  
Vol 81 (3) ◽  
pp. 230-236 ◽  
Author(s):  
Marianne Lucas ◽  
Tomoji Mashimo ◽  
Marie‐Pascale Frenkiel ◽  
Dominique Simon‐Chazottes ◽  
Xavier Montagutelli ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Oligoadenylate Synthetase ◽  
West Nile

scholarly journals Stress hormones predict a host superspreader phenotype in the West Nile virus system

2017 ◽  
Vol 284 (1859) ◽  
pp. 20171090 ◽  
Author(s):  
Stephanie S. Gervasi ◽  
Sarah C. Burgan ◽  
Erik Hofmeister ◽  
Thomas R. Unnasch ◽  
Lynn B. Martin
Keyword(s):  
West Nile Virus ◽  
Stress Hormones ◽  
Activity Levels ◽  
West Nile ◽  
Viral Loads ◽  
Pathogen Dynamics ◽  
Host Competence ◽  
Host Mortality ◽  
Host Metabolism ◽  
Virus System

Glucocorticoid stress hormones, such as corticosterone (CORT), have profound effects on the behaviour and physiology of organisms, and thus have the potential to alter host competence and the contributions of individuals to population- and community-level pathogen dynamics. For example, CORT could alter the rate of contacts among hosts, pathogens and vectors through its widespread effects on host metabolism and activity levels. CORT could also affect the intensity and duration of pathogen shedding and risk of host mortality during infection. We experimentally manipulated songbird CORT, asking how CORT affected behavioural and physiological responses to a standardized West Nile virus (WNV) challenge. Although all birds became infected after exposure to the virus, only birds with elevated CORT had viral loads at or above the infectious threshold. Moreover, though the rate of mortality was faster in birds with elevated CORT compared with controls, most hosts with elevated CORT survived past the day of peak infectiousness. CORT concentrations just prior to inoculation with WNV and anti-inflammatory cytokine concentrations following viral exposure were predictive of individual duration of infectiousness and the ability to maintain physical performance during infection (i.e. tolerance), revealing putative biomarkers of competence. Collectively, our results suggest that glucocorticoid stress hormones could directly and indirectly mediate the spread of pathogens.

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