c-FLIP facilitates ZIKV infection by mediating caspase-8/3-dependent apoptosis

by Shengze Zhang, Nina Li, Shu Wu, Ting Xie, Qiqi Chen, Jiani Wu, Shike Zeng, Lin Zhu, Shaohui Bai, Haolu Zha, Weijian Tian, Nan Wu, Xuan Zou, Shisong Fang, Chuming Luo, Mang Shi, Caijun Sun, Yuelong Shu, Huanle Luo

c-FLIP functions as a dual regulator of apoptosis and inflammation, yet its implications in Zika virus (ZIKV) infection remain partially understood, especially in the context of ZIKV-induced congenital Zika syndrome (CZS) where both apoptosis and inflammation play pivotal roles. Our findings demonstrate that c-FLIP promotes ZIKV infection in placental cells and myeloid-derived macrophages, involving inflammation and caspase-8/3-mediated apoptosis. Moreover, our observations reveal that c-FLIP augments ZIKV infection in multiple tissues, including blood cell, spleen, uterus, testis, and the brain of mice. Notably, the partial deficiency of c-FLIP provides protection to embryos against ZIKV-induced CZS, accompanied by a reduction in caspase-3-mediated apoptosis. Additionally, we have found a distinctive parental effect of c-FLIP influencing ZIKV replication in fetal heads. In summary, our study reveals the critical role of c-FLIP as a positive regulator in caspase-8/3-mediated apoptosis during ZIKV infection, significantly contributing to the development of CZS.