TLR3 activation by Zika virus stimulates inflammatory cytokine production which dampens the antiviral response induced by RIG-I-like receptors.

Infection with the Zika virus (ZIKV), a member of the Flaviviridae family, can cause serious neurological disorders, most notably microcephaly in newborns. Here we investigated the innate immune response to ZIKV infection in cells of the nervous system. In human neural progenitor cells (hNPCs), a target for ZIKV infection and likely involved in ZIKV-associated neuropathology, viral infection failed to elicit an antiviral interferon (IFN) response. However, pharmacological inhibition of TLR3 partially restored this deficit. Analogous results were obtained in human iPSC-derived astrocytes, which are capable of mounting a strong antiviral cytokine response. There, ZIKV is sensed by both RIG-I and MDA5 and induces an IFN response as well as expression of pro-inflammatory cytokines such as interleukin-6 (IL-6). Upon inhibition of TLR3, also in astrocytes the antiviral cytokine response was enhanced, whereas amounts of pro-inflammatory cytokines were reduced. To study the underlying mechanism, we used human epithelial cells as an easy to manipulate model system. We found that ZIKV is sensed in these cells by RIG-I to induce a robust IFN response and by TLR3 to trigger the expression of pro-inflammatory cytokines, including IL-6. ZIKV induced upregulation of IL-6 activated the STAT3 pathway, which decreased STAT1 phosphorylation in a SOCS-3 dependent manner, thus reducing the IFN response. In conclusion, we show that TLR3 activation by ZIKV suppresses IFN responses triggered by RIG-I-like receptors.ImportanceZika virus (ZIKV) has a pronounced neurotropism and infections with this virus can cause serious neurological disorders, most notably microcephaly and the Guillain-Barré syndrome. Our studies reveal that during ZIKV infection, recognition of viral RNA by TLR3 enhances the production of inflammatory cytokines and suppresses the interferon response triggered by RIG-I-like receptors (RLR) in a SOCS3-dependent manner, thus facilitating virus replication. The discovery of this crosstalk between antiviral (RLR) and inflammatory (TLR) responses may have important implications for our understanding of ZIKV-induced pathogenesis.