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

Summary Zika virusis a pathogen that poses serious consequences, including congenital microcephaly. Although many viruses reprogramhost cell metabolism, whether Zika virusalters cellular metabolism and the functional consequences of Zika-induced metabolic changes remain unknown. Here, we show that Zika virusinfection differentially reprogramsglucose metabolism in human versus C6/36 mosquito cells by increasing glucose use in the tricarboxylic acidcycle in human cells versus increasing glucose use in the pentose phosphate pathwayin 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. AMPKis also phosphorylated in Zika virus-infected mouse brain. Inhibiting AMPKin human cells decreases Zika virus-mediated cell death, whereas activating AMPKin mosquito cells promotes Zika virus-mediated cell death. These findings suggest that the differential metabolic reprogrammingduring Zika virusinfection of human versus mosquito cells determineswhether cell death occurs.