Dengue Virus Inhibits Alpha Interferon Signaling by Reducing STAT2 Expression

Jones, Meleri; Davidson, Andrew D.; Hibbert, Linda; Gruenwald, Petra; Schlaak, Joerg F.; Ball, Simon; Foster, Graham R.; Jacobs, Michael

doi:10.1128/jvi.79.9.5414-5420.2005

Cited by 238 publications

(214 citation statements)

References 45 publications

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“…Gene expression studies indicated that STAT2 overexpression is not driving antiviral signaling like IRF1. Previous studies have shown that the DENV NS5 polymerase potently antagonizes IFN signaling by mediating STAT2 degradation (35,36). Our data fit this mechanism and suggest that STAT2 overexpression may be sufficient to squelch DENV replication by stoichiometrically overcoming the viral NS5 polymerase.…”

Section: Resultssupporting

confidence: 72%

Dengue reporter viruses reveal viral dynamics in interferon receptor-deficient mice and sensitivity to interferon effectors in vitro

Schoggins

Dorner

Feulner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

172

175

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Dengue virus (DENV) is a global disease threat for which there are no approved antivirals or vaccines. Establishing state-of-the-art screening systems that rely on fluorescent or luminescent reporters may accelerate the development of anti-DENV therapeutics. However, relatively few reporter DENV platforms exist. Here, we show that DENV can be genetically engineered to express a green fluorescent protein or firefly luciferase. Reporter viruses are infectious in vitro and in vivo and are sensitive to antiviral compounds, neutralizing antibodies, and interferons. Bioluminescence imaging was used to follow the dynamics of DENV infection in mice and revealed that the virus localized predominantly to lymphoid and gut-associated tissues. The high-throughput potential of reporter DENV was demonstrated by screening a library of more than 350 IFN-stimulated genes for antiviral activity. Several antiviral effectors were identified, and they targeted DENV at two distinct life cycle steps. These viruses provide a powerful platform for applications ranging from validation of vaccine candidates to antiviral discovery. Flaviviridae family that causes significant morbidity and mortality worldwide. Each year, over 50 million people are affected by dengue fever, and ∼500,000 are hospitalized with the more severe dengue hemorrhagic fever (1). The virus is endemic to tropical environments in Southeast Asia, the Pacific, and the Americas, and has recently reemerged as far north as southern Florida (2). Currently, no vaccines or antivirals have been approved for prevention or treatment of DENV infection.Four genetically and antigenically distinct DENV serotypes circulate, and each can be isolated from infected human sera and propagated in cell culture. The pathogenesis and immune response to patient-derived virus can be studied in vitro and in vivo by quantifying viral genomes or antigens. These detection methods are also used to study the molecular virology of DENV with reagents such as virus-like particles (VLPs) and subgenomic replicons. In some cases, VLPs and subgenomic replicons have been engineered to take advantage of reporter proteins, such as luciferase, which can be used in high-throughput screening platforms for discovery of inhibitors of viral entry or replication (3). A caveat to these tools is the inability to fully recapitulate the entire viral life cycle. This can be overcome by launching virus production from full-length infectious molecular clones, which have been generated for DENV serotypes 1, 2, and 4 (4-6).Full-length flavivirus infectious clones are often difficult to work with, largely due to instability in various bacterial cell lines and the inability to rescue sufficient quantities of DNA for downstream applications (7). Additionally, mutagenesis of viral sequences may result in disruption of the various long-range interactions required for establishment of a productive replication complex (8-10). Thus, strategies to generate infectious viruses expressing heterologous sequences have to contend with both sub...

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Section: Resultssupporting

confidence: 72%

Dengue reporter viruses reveal viral dynamics in interferon receptor-deficient mice and sensitivity to interferon effectors in vitro

Schoggins

Dorner

Feulner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

172

175

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“…Similar to other known flaviviruses, DTMUV has an approximately 11 kb single-stranded positive-sense RNA genome, which contains a single ORF that encodes three structural proteins (C, prM, and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5), flanked by the 5¢ and 3¢ untranslated regions (UTRs). The structural proteins are supposed to be involved in cellular attachment, membrane fusion and virion assembly, and the nonstructural proteins are responsible for genome replication and counteraction of host immunity, in similar mechanisms to other known pathogenic flaviviruses (Avirutnan et al, 2010;Best et al, 2005;Crook et al, 2014;Jones et al, 2005;Munoz-Jordan et al, 2003;Werme et al, 2008). DTMUV is highly pathogenic for ducks, and exhibited neurotropic effects in a mouse model Tang et al, 2013).…”

mentioning

confidence: 99%

In vitro and in vivo characterization of chimeric duck Tembusu virus based on Japanese encephalitis live vaccine strain SA14-14-2

Wang

Liu

et al. 2016

Journal of General Virology

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“…Although the functions of NS2A, NS4A, and NS4B have not yet been fully elucidated, several studies suggest that they may anchor the viral replicase proteins to cellular membranes, 52 assist in virion assembly, 53,54 and lead to inhibition of the interferon a/β response. [55][56][57][58] It has been reported that NS4A may play a role in induction of membrane alterations, assumed to serve as a scaffold for the formation of the viral replicase complex, 59 and the interaction between NS1 and NS4A, which is critical for viral RNA replication. 59,60 Mutations in the NS2A protein that diminish its ability to inhibit the host interferon response could contribute to the non-predominant status of genotype III viruses.…”

mentioning

confidence: 99%

Comparative Analysis of Full-Length Genomic Sequences of 10 Dengue Serotype 1 Viruses Associated with Different Genotypes, Epidemics, and Disease Severity Isolated in Thailand over 22 Years

Tang

Rodpradit²,

Chinnawirotpisan³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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Abstract. Comparative sequence analysis was performed on the full-length genomic sequences of 10 representative dengue virus serotype 1 (DENV-1) strains sampled from patients at Children's Hospital, Bangkok, Thailand over a 22-year period, which represented different epidemics, disease severity, and sampling time. The results showed remarkable inter-genotypic variation between predominant and non-predominant genotypes and genotype-specific amino acids and nucleotides throughout the entire viral genome except for the 5′-non-translated region. The frequency of intra-genotypic variation was correlated with dengue transmission rate and sampling time. The 5′-non-translated region of all 10 viruses was highly conserved for predominant and non-predominant genotypes and NS2B was the most conserved protein. Some intra-genotypic substitutions of amino acids and nucleotides in predominant genotype strains were fixed in the viral genome since 1994, which indicated that the evolution of predominant genotype strains in situ over time might contribute to increased virus fitness important for sustaining dengue epidemics in Thailand.

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Dengue Virus Inhibits Alpha Interferon Signaling by Reducing STAT2 Expression

Cited by 238 publications

References 45 publications

Dengue reporter viruses reveal viral dynamics in interferon receptor-deficient mice and sensitivity to interferon effectors in vitro

Dengue reporter viruses reveal viral dynamics in interferon receptor-deficient mice and sensitivity to interferon effectors in vitro

In vitro and in vivo characterization of chimeric duck Tembusu virus based on Japanese encephalitis live vaccine strain SA14-14-2

Comparative Analysis of Full-Length Genomic Sequences of 10 Dengue Serotype 1 Viruses Associated with Different Genotypes, Epidemics, and Disease Severity Isolated in Thailand over 22 Years

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