Zika virus inhibits cell death by inhibiting the expression of NLRP3 and A20

Zika virus (ZIKV) is associated with microcephaly in neonates and neurological disorders in adults. Chronic ZIKV infection has been identified in the testes, indicating that the virus can lead to prolonged illness, yet its pathogenesis remains poorly understood. Here, we found that ZIKV infection does not induce significant cell death in mouse macrophages despite the critical role that cell death plays in the antiviral immune response. Furthermore, we discovered that ZIKV infection impairs the activation of the NLPR3-dependent inflammasome and inhibits apoptosis. Consequently, we investigated the regulatory mechanism of the NLRP3 inflammasome and apoptosis in the context of ZIKV infection. Our results revealed significant reductions in the protein expression levels of NLRP3 and A20, attributable to post-transcriptional or translational effects during ZIKV infection. These findings suggest that ZIKV infection may disrupt cell death pathways, leading to its pathogenicity.IMPORTANCEZika virus (ZIKV), first isolated from a nonhuman primate in Africa in 1947, was relatively understudied until 2016. By then, ZIKV had already been reported in more than 20 countries and territories. The infection poses a significant risk, as it is associated with microcephaly in infants and neurological disorders in adults; however, the underlying mechanisms responsible for these severe outcomes remain unclear. In this study, we demonstrate that ZIKV infection significantly reduces the expression of NLRP3 and A20 proteins through post-transcriptional or translational processes, which leads to inhibited cell death. These findings are critical because cell death plays a vital role in the host's antiviral immune response. Our findings highlight how ZIKV infection compromises essential cell death pathways, raising serious concerns about its pathogenesis. A comprehensive understanding of this disruption is vital for developing targeted interventions to mitigate the virus' impact on public health.