The 2′,5′-Oligoadenylate Synthetase 1b Is a Potent Inhibitor of West Nile Virus Replication Inside Infected Cells

Abstract

The 2,5-oligoadenylate synthetase (OAS) proteins associated with endoribonuclease RNase L are components of the interferonregulated OAS/RNase L system, which is an RNA decay pathway known to play an important role in the innate antiviral immunity. A large body of evidence suggests a critical role for the 1b isoform of the mouse Oas gene (Oas1b) in resistance to West Nile virus (WNV) infection in vivo. WNV is a positive, single-stranded RNA virus responsible for severe encephalitis in a large range of animal species and humans. To investigate the molecular basis for the sensitivity of WNV to the Oas1b antiviral pathway, we established a stable mouse fibroblastic cell clone that up-regulates Oas1b protein expression under the control of the Tet-Off expression system. We showed that murine cells respond to Oas1b expression by efficiently inhibiting WNV replication. The antiviral action of Oas1b was essentially restricted to the early stages in virus life cycle. We found that the inability of WNV to productively infect the Oas1b-expressing cells was attributable to a dramatic reduction in positive-stranded viral RNA level. Thus, Oas1b represents an antiviral pathway that exerts its inhibitory effect on WNV replication by preventing viral RNA accumulation inside infected cells. The emergence of virulent variant of West Nile virus (WNV)6 has been associated with a dramatic increase in severity of infection in humans, thus drawing the attention to West Nile illness as a public health concern (1). WNV is an enveloped, plus-stranded RNA virus that belongs to the flavivirus genus (family Flaviviridae) (2). WNV infects the central nervous system and causes viral encephalitis in a large range of animal species (1). The virion is composed of three structural proteins: C (core protein), M (membrane protein), and E (envelope protein). Translation of genomic RNA results in the synthesis of structural proteins C, prM (the intracellular precursor of M) and E, and seven non-structural (NS) proteins NS1 to NS5 (2). In the cytoplasm, the RNA replication begins with the synthesis of negative-and positive-stranded genome-length RNA (2).The rapid initiation of innate antiviral mechanisms mediated by Type-I IFNs (IFN-␣/␤) may be essential for protection against WNV infection (3-5). We reported that IFN-␣/␤ receptor-deficient mice have an increased susceptibility to WNV as compared with immunocompetent mice (6). IFN-␣ and -␤ are able to trigger the activation of a specific signal transduction pathway leading to induction of IFN-stimulated genes that are responsible for the establishment of an antiviral state (7). The IFN-induced proteins believed to affect virus replication in single cells are the RNA-specific adenosine deaminase, the proteins of the Mx family, the double-stranded RNA-dependent protein kinase, and the 2Ј,5Ј-oligoadenylate synthetase (OAS) family associated to endoribonuclease RNase L (OAS/RNase L system) (7).The OAS/RNase L system is an RNA decay pathway known to play an important role in the established endogenous antiv...

Distinct Antiviral Roles for Human 2′,5′-Oligoadenylate Synthetase Family Members against Dengue Virus Infection

“…Furthermore, genetic knock-in of the Oas1b resistance allele into a susceptible mouse strain confers resistance to the yellow fever virus (8). In vitro data also show that cells expressing wild-type OAS1b but not C-terminally truncated OAS1b efficiently block WNV replication (9,10). Thus, in vivo and in vitro experiments indicate that mouse Oas1b is an important genetic factor in flavivirus resistance.…”

TLR3 Ligation Activates an Antiviral Response in Human Fetal Astrocytes: A Role for Viperin/cig5

“…The NS3/4A protein complex of hepatitis C virus also blocks phosphorylation of IRF3 (34). Among the ISG, the antiviral activity of 2Ј5ЈOAS has been wellcharacterized (35,36), however, the complete spectrum of ISG with potential antiviral activity remains to be defined. In this context, it is of interest to note that the microarray analysis of our pIC-activated astrocytes identified viperin/cig5 as one of the most highly expressed genes.…”

West Nile virus meningoencephalitis

“…2 -5 -Oas1b is also a potent inhibitor of WNV replication in infected cells. 39 The role of the Oas system in human susceptibility to WNV infection is unknown. In one recent study, however, differences were observed in the frequency distribution of at least one polymorphism in OAS genes in hospital ized patients with WNV infection compared with controls, raising the possibility that the Oas system also has a role in human susceptibility to WNV infection.…”