Laboratory of Persistent Viral Diseases, Rocky Mountain
Laboratories, NIAID, NIH, 903 S. Fourth St., Hamilton, MT59840.
sbest@niaid.nih.gov.
The tick-borne encephalitis (TBE) complex of viruses, genus Flavivirus, can cause severe encephalitis, meningitis,
and/or hemorrhagic fevers. Effective interferon (IFN) responses are
critical to recovery from infection with flaviviruses,
and the mosquito-borne flaviviruses can inhibit
this response. However, little is known about interactions between IFN
signaling and TBE viruses. Langat virus (LGTV), a
member of the TBE complex of viruses, was found to be highly sensitive to
the antiviral effects of IFN. However, LGTV infection inhibited IFN-induced
expression of a reporter gene driven by either IFN-alpha/beta- or
IFN-gamma-responsive promoters. This indicated that LGTV can inhibit the
IFN-mediated JAK-STAT (Januskinase-signal
transducer and activator of transcription) pathway of signal transduction.
The mechanism of inhibition was due to blocks in the phosphorylation
of both Januskinases,
Jak1 and Tyk2, during IFN-alpha signaling and at least a failure of Jak1 phosphorylation following IFN-gamma stimulation. To
determine the viral protein(s) responsible, we individually expressed all
nonstructural (NS) proteins and examined their ability to inhibit signal
transduction. Expression of NS5 alone inhibited STAT1 phosphorylation
in response to IFN, thus identifying NS5 as a potential IFN antagonist.
Examination of interactions between NS5 and cellular proteins revealed that
NS5 associated with IFN-alpha/beta and -gamma receptor complexes.
Importantly, inhibition of JAK-STAT signaling and NS5-IFN receptor
interactions were demonstrated in LGTV-infected human monocyte-derived
dendritic cells, important target cells for early
virus replication. Because NS5 may interfere with both innate and acquired
immune responses to virus infection, this protein may have a significant
role in viral pathogenesis.
