Caspase-1/11 Controls Zika Virus Replication in Astrocytes by Regulating Glycolytic Metabolism

Abstract

The Zika virus (ZIKV) poses a significant threat due to its association with severe neurological complications, particularly during pregnancy. Although viruses exhibit tropism for neural cells, including astrocytes, the role of these cells in controlling ZIKV replication remains unclear. In this study, we demonstrated that ZIKV induces caspase-1 activation in primary astrocytes despite the absence of classical signs of inflammasome activation. Caspase-1/11^−/− astrocytes exhibit heightened permissiveness to viral replication, accompanied by overactivation of glycolytic metabolism. Inhibition of glycolysis reversed the susceptibility of caspase-1/11^−/− astrocytes to ZIKV infection. Protein network analysis revealed mTORC as a link between proteins involved in glycolysis and caspase-1, and mTORC inhibition also suppressed viral replication. Furthermore, we found that the impact of caspase-1/11 on astrocytes is dependent on pyruvate transport to mitochondria for viral replication, emphasizing the role of the mTORC/glycolytic pathway/pyruvate axis in the caspase-1/11-mediated control of ZIKV. Overall, our findings elucidate a caspase-1/11-dependent microbicidal mechanism in astrocytes, providing insights into potential therapeutic targets for ZIKV infection.