Jones, M; Davidson, A; Hibbert, L; Gruenwald, P; Schlaak, J; Ball, S; Foster, G; Jones, M; Davidson, A; Hibbert, L; Gruenwald, P; Schlaak, J; Ball, S; Foster, G; Jacobs, M; - view fewer (2005) Dengue virus inhibits alpha interferon signaling by reducing STAT2 expression. Journal of Virology , 79 (9) pp. 5414-5420. 10.1128/JVI.79.9.5414-5420.2005.

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Abstract

Type 1 interferons (IFN-?/?) are key mediators of innate antiviral responses but havelittle effect on established replication of dengue viruses, which are mosquito-borneflaviviruses of immense global health importance. Understanding how the IFN systemis inhibited in dengue virus-infected cells would provide critical insight into diseasepathogenesis. In a recent study analyzing the ability of individual dengue virusencodedproteins to antagonize the IFN response, non-structural (NS) protein 4B, andpossibly NS2A and NS4A, were identified as candidate IFN antagonists. In monkeycells, NS4B appeared to inhibit both IFN-?/? and IFN-? signal transductionpathways, which are distinct but overlapping (Munoz-Jordan, J. L., G. G. Sanchez-Burgos, M. Laurent-Rolle, and A. Garcia-Sastre. 2003. Proc Natl Acad Sci U S A100:14333-8). Here we examine the effects of dengue on the human IFN system usingcell lines that are stably transfected with self-replicating subgenomic dengue RNA(replicons) and express all the dengue non-structural proteins together. We show thatin replicon-containing cells dengue RNA replication and replication ofencephalomyocarditis virus, an IFN-sensitive virus, are resistant to the antiviraleffects of IFN-?. The presence of dengue replicons reduces global IFN-?-stimulatedgene expression, and specifically inhibits IFN-?, but not IFN-?, signal transduction.In cells containing replicons, or infected with dengue virus, we found reduced levelsof signal transducer and activator of transcription (STAT) 2, which is a keycomponent of IFN-? but not IFN-? signaling. Collectively, these data show thatdengue virus is capable of subverting the human IFN response by down-regulatingSTAT2 expression.

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