TY - JOUR TI - Zika virus causes placental pyroptosis and associated adverse fetal outcomes by activating GSDME AU - Zhao, Zikai AU - Li, Qi AU - Ashraf, Usama AU - Yang, Mengjie AU - Zhu, Wenjing AU - Gu, Jun AU - Chen, Zheng AU - Gu, Changqin AU - Si, Youhui AU - Cao, Shengbo AU - Ye, Jing A2 - Carette, Jan E A2 - Taniguchi, Tadatsugu VL - 11 PY - 2022 DA - 2022/08/16 SP - e73792 C1 - eLife 2022;11:e73792 DO - 10.7554/eLife.73792 UR - https://doi.org/10.7554/eLife.73792 AB - Zika virus (ZIKV) can be transmitted from mother to fetus during pregnancy, causing adverse fetal outcomes. Several studies have indicated that ZIKV can damage the fetal brain directly; however, whether the ZIKV-induced maternal placental injury contributes to adverse fetal outcomes is sparsely defined. Here, we demonstrated that ZIKV causes the pyroptosis of placental cells by activating the executor gasdermin E (GSDME) in vitro and in vivo. Mechanistically, TNF-α release is induced upon the recognition of viral genomic RNA by RIG-I, followed by activation of caspase-8 and caspase-3 to ultimately escalate the GSDME cleavage. Further analyses revealed that the ablation of GSDME or treatment with TNF-α receptor antagonist in ZIKV-infected pregnant mice attenuates placental pyroptosis, which consequently confers protection against adverse fetal outcomes. In conclusion, our study unveils a novel mechanism of ZIKV-induced adverse fetal outcomes via causing placental cell pyroptosis, which provides new clues for developing therapies for ZIKV-associated diseases. KW - Zika virus KW - pyroptosis KW - gasdermin E KW - placental injury JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -