Dengue virus inhibits alpha interferon signaling by reducing STAT2 expression.
Alpha/beta interferon (IFN-alpha/beta) is a key mediator of innate antiviral responses but has little effect on the established replication of dengue viruses, which are mosquito-borne flaviviruses of immense global health importance. Understanding how the IFN system is inhibited in dengue virus-infected cells would provide critical insights into disease pathogenesis. In a recent study analyzing the ability of individual dengue virus-encoded proteins to antagonize the IFN response, nonstructural (NS) protein 4B and possibly NS2A and NS4A were identified as candidate IFN antagonists. In monkey cells, NS4B appeared to inhibit both the IFN-alpha/beta and IFN-gamma signal transduction pathways, which are distinct but overlapping (J. L. Munoz-Jordan, G. G. Sanchez-Burgos, M. Laurent-Rolle, and A. Garcia-Sastre, Proc. Natl. Acad. Sci. USA 100:14333-14338, 2003). For this study, we examined the effects of dengue virus on the human IFN system, using cell lines that were stably transfected with self-replicating subgenomic dengue virus RNA (replicons) and that expressed all of the dengue virus nonstructural proteins together. We show here that in replicon-containing cells dengue virus RNA replication and the replication of encephalomyocarditis virus, an IFN-sensitive virus, are resistant to the antiviral effects of IFN-alpha. The presence of dengue virus replicons reduces global IFN-alpha-stimulated gene expression and specifically inhibits IFN-alpha but not IFN-gamma signal transduction. In cells containing replicons or infected with dengue virus, we found reduced levels of signal transducer and activator of transcription 2 (STAT2), which is a key component of IFN-alpha but not IFN-gamma signaling. Collectively, these data show that dengue virus is capable of subverting the human IFN response by down-regulating STAT2 expression.
Jones
Meleri
M
DDRC, Queen Mary's School of Medicine and Dentistry, Royal Free & University College Medical School, Rowland Hill St., London NW3 2PF, United Kingdom.
Davidson
Andrew
A
Hibbert
Linda
L
Gruenwald
Petra
P
Schlaak
Joerg
J
Ball
Simon
S
Foster
Graham R
GR
Jacobs
Michael
M
D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003716:Dengue Virus / Q000472:pathogenicity / Q000502:physiology*; D015536:Down-Regulation; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D012093:Replicon / Q000502:physiology; D050795:STAT2 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D015534:Trans-Activators