Differential Metabolic Reprogramming by Zika Virus Promotes Cell Death in Human versus Mosquito Cells

Zika virus is a pathogen that poses serious consequences, including congenital microcephaly. Although many viruses reprogram host cell metabolism, whether Zika virus alters cellular metabolism and the functional consequences of Zika-induced metabolic changes remain unknown. Here, we show that Zika virus infection differentially reprograms glucose metabolism in human versus C6/36 mosquito cells by increasing glucose use in the tricarboxylic acid cycle in human cells versus increasing glucose use in the pentose phosphate pathway in mosquito cells. Infection of human cells selectively depletes nucleotide triphosphate levels, leading to elevated AMP/ATP ratios, AMP-activated protein kinase (AMPK) phosphorylation, and caspase-mediated cell death. AMPK is also phosphorylated in Zika virus-infected mouse brain. Inhibiting AMPK in human cells decreases Zika virus-mediated cell death, whereas activating AMPK in mosquito cells promotes Zika virus-mediated cell death. These findings suggest that the differential metabolic reprogramming during Zika virus infection of human versus mosquito cells determines whether cell death occurs. [Display omitted] •ZIKV infection differentially reprograms human versus C6/36 mosquito cell metabolism•ZIKV infection depletes nucleoside triphosphates and activates AMPK in human cells•ZIKV infection of mouse brain leads to AMPK phosphorylation in vivo•AMPK activation contributes to ZIKV-induced apoptosis in human cells Thaker et al. report that Zika virus differentially rewires the metabolism of human cells and mosquito cells during infection and that this differential metabolic rewiring contributes to the cell death observed in Zika-virus-infected human cells and survival in Zika-virus-infected mosquito cells.