Infection with the Zika virus (ZIKV), a member of the Flaviviridae family, can cause serious neurological disorders, most notably microcephaly in newborns. In this study, 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 Toll-like receptor 3 (TLR3) partially restored this deficit. Analogous results were obtained in human induced pluripotent stem cell (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 proinflammatory cytokines, such as interleukin-6 (IL-6). Upon inhibition of TLR3, also in astrocytes the antiviral cytokine response was enhanced, whereas amounts of proinflammatory 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 proinflammatory cytokines, including IL-6. ZIKV-induced upregulation of IL-6 activated the STAT3 pathway, which decreased STAT1 phosphorylation in a SOCS3-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 (RLR). [ABSTRACT FROM AUTHOR]