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.

寨卡病毒（ZIKV）是一种蚊子传播的黄病毒，与严重的新生儿出生缺陷有关，但其致病机理尚不完全清楚。ZIKV与黄热病病毒（YFV）和登革热病毒（DENV）具有序列同源性和早期临床表现，并且在城市周期中都是由相同种类的蚊子传播的。然而，极少有人报道YFV和DENV引起先天性疾病。在这里，我们比较了在人单核细胞（THP-1）和早孕滋养细胞（HTR-8）中YFV17D和DENV-4与当代ZIKV株（FSS13025）的感染情况。我们的结果表明，对于这两种细胞，所有三种病毒都具有相似的嗜性。然而，ZIKV在单核细胞和外周血单核细胞中诱导了强烈的1型IFN以及炎性细胞因子和趋化因子的产生。此外，滋养细胞中的ZIKV感染诱导较低的IFN和较高的炎性免疫反应。已知胎盘发炎会导致早产儿脑部受损的风险。对Toll样受体（TLR）3和TLR8的抑制均消除了ZIKV感染的滋养细胞中的炎症细胞因子反应。我们的发现确定了母体免疫激活与ZIKV诱导的先天性疾病之间的潜在联系，以及针对TLR介导的胎盘炎症反应的潜在治疗策略。