Flavivirus NS5 interacts with HSP90 to broadly inhibit JAK/STAT signalling: a non-specific mechanism that has implications for Zika virus-driven microencephaly

Flaviviruses (including West Nile virus and Zika virus (ZIKV)) disrupt host interferon signalling defenses to promote pathogenesis. Diverse mechanisms of this Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling inhibition have been proposed. We infected cells with flaviviruses at high MOI and assessed their capacity to respond to cytokines. Surprisingly, we revealed that flaviviruses inhibit JAK/STAT signalling responses to many different cytokines beyond just type I interferons, including IL-6, IL-4, and IFN-lambda. Flaviviruses achieve this broad inhibition via viral nonstructural protein 5 (NS5) interaction with host heat shock protein 90 (HSP90). The interaction between HSP90 and NS5 is associated with reduced HSP90-JAK1 association and a loss of abundance of JAK family proteins (which are all clients of this chaperone). Decreased JAK protein abundance led to inhibited signal transmission, with a failure to phosphorylate STAT proteins in response to cytokine stimuli, and a failure to express cytokine-dependent genes. This general blockade in signalling was demonstrated to hold unforeseen importance for disease manifestations. Neural stem cells infected with ZIKV displayed early deficits in neurotrophic cytokine-driven astroglial and neuronal differentiation. It is therefore likely that this mechanism contributes to ZIKV inhibition of foetal brain development leading to microencephaly. Thus, this novel HSP90 interaction axis constitutes a promising target for antiviral development aiming to disrupt viral NS5 interaction with HSP90.