Shuqing Zhang, Delin Chen, Kexin Zhang, Minjie Liu, H. Liang, Linyue Liang, Jingyao Liang, Minqi Liang, Shu An, Mingcui Lyu, Zhu Junying, Shangwei Li, Dingwen Hu, Xun Zhu, Jueheng Wu, Zhenjian He, Mengfeng Li
ABSTRACT Infection by the Zika virus (ZIKV) during pregnancy can cause congenital Zika syndrome (CZS) or other central nervous system conditions in infants, underscoring the importance of understanding the role of ZIKV-induced placental damage in the development of CZS. Here, we established a ZIKV-infected pregnant mouse model and examined the pathological changes in the placenta following ZIKV infection. We found that ZIKV infection induces severe placental inflammation associated with trophoblast PANoptosis. Specifically, ZIKV activates RIG-I and recruits ASC, caspase-1, NLRP3, caspase-8, and RIPK1 to form a PANoptosome complex, leading to the activation of PANoptosis. Moreover, the combined use of Z-VAD-FMK with GSK872 or with the RIG-I inhibitor RIG012 robustly suppressed ZIKV-induced cell death, attenuated the inflammatory response in trophoblast cells and the placenta induced by ZIKV infection. Collectively, we elucidate a previously unrecognized mechanism by which ZIKV infection causes severe placental inflammation by activating PANoptosis and provide a foundation for the potential application of anti-PANoptotic therapy against ZIKV-associated diseases. IMPORTANCE Zika virus (ZIKV), a mosquito-borne virus, has caused significant disease in humans during outbreaks over the last decade. Currently, there is no approved preventive vaccine or specific therapeutic drug against ZIKV. The World Health Organization declared a Public Health Emergency of International Concern regarding microcephaly and other neurological disorders caused by ZIKV during pregnancy in 2016, highlighting the importance of understanding the role of the maternal-fetal barrier in this viral disease. The mechanism by which ZIKV causes placental pathogenesis, however, remains unclear. In this study, our data elucidate a previously unrecognized mechanism underlying ZIKV infection that causes severe placental inflammation by activating PANoptosis. Furthermore, we propose a treatment that effectively inhibits ZIKV-induced PANoptosis and attenuates the inflammatory response in trophoblast cells in vitro and in vivo .