Dysregulated Metabolism Underpins Zika Virus Infection-Associated Impairment in Fetal Development

Abstract

Zika virus (ZIKV) is an Aedes mosquito-borne flavivirus that causes debilitating congenital and developmental disorders. No licensed ZIKV vaccine or treatment exist, due largely to an incomplete understanding of ZIKV pathogenesis. In this study, we used a panel of ZIKV strains, including a pair that differ by just a single amino acid substitution (phenylalanine to leucine substitution, M-F37L) in the membrane (M) protein, and coupled these with unbiased whole genome gene expression studies to demarcate the border between attenuated and pathogenic infection. We identified infection-induced metabolic dysregulation as a minimal set of host alterations that differentiated attenuated from pathogenic ZIKV strains. Glycolytic rewiring reduced availability of tricarboxylic acid (TCA) cycle substrates, resulting in impaired oxidative phosphorylation and mitochondrial dysfunction that triggered inflammation and apoptosis in pathogenic but not attenuated ZIKV strains. Exogenous supplementation of pyruvate and glutamine that feed directly into the TCA cycle, reduced inflammatory and apoptotic responses induced by wild-type ZIKV infection. Critically, pyruvate supplementation to ZIKV-infected dams prevented gross fetal developmental abnormalities and rescued fetal growth. Our findings thus pinpoint dysregulated metabolism as an underpinning of ZIKV pathogenicity and that pyruvate supplementation to expectant women could be explored as a prophylaxis for congenital Zika syndrome.