LAUSR

ABSTRACT Zika virus (ZIKV) is a mosquito‐borne flavivirus associated with severe neonatal birth defects, but the causative mechanism is incompletely understood. ZIKV shares sequence homology and early clinical manifestations with yellow fever virus (YFV) and dengue virus (DENV) and are all transmitted in urban cycles by the same species of mosquitoes. However, YFV and DENV have been rarely reported to cause congenital diseases. Here, we compared infection with a contemporary ZIKV strain (FSS13025) to YFV17D and DENV‐4 in human monocytic cells (THP‐1) and first‐trimester trophoblasts (HTR‐8). Our results suggest that all three viruses have similar tropisms for both cells. Nevertheless, ZIKV induced strong type 1 IFN and inflammatory cytokine and chemokine production in monocytes and peripheral blood mononuclear cells. Furthermore, ZIKV infection in trophoblasts induced lower IFN and higher inflammatory immune responses. Placental inflammation is known to contribute to the risk of brain damage in preterm newborns. Inhibition of toll‐like receptor (TLR)3 and TLR8 each abrogated the inflammatory cytokine responses in ZIKV‐infected trophoblasts. Our findings identify a potential link between maternal immune activation and ZIKV‐induced congenital diseases, and a potential therapeutic strategy that targets TLR‐mediated inflammatory responses in the placenta. HighlightsZIKV, YFV and DENV have similar tropisms for human monocytic cells and first‐trimester trophoblasts.ZIKV induced strong anti‐viral immune responses in human monocytes and peripheral blood mononuclear cells.ZIKV infection in trophoblasts induced lower IFN and higher inflammatory immune Responses.TLRs 3 and 8 mediate inflammatory cytokine responses in trophoblasts during ZIKV infection.