Dysregulated metabolism underpins Zika-virus-infection-associated impairment in fetal development

Cell Rep. 2021 Dec 14;37(11):110118. doi: 10.1016/j.celrep.2021.110118.


Zika virus (ZIKV) is an Aedes-mosquito-borne flavivirus that causes debilitating congenital and developmental disorders. Improved understanding of ZIKV pathogenesis could assist efforts to fill the therapeutic and vaccine gap. We use several ZIKV strains, including a pair differing by a single phenylalanine-to-leucine substitution (M-F37L) in the membrane (M) protein, coupled with unbiased genomics to demarcate the border between attenuated and pathogenic infection. We identify infection-induced metabolic dysregulation as a minimal set of host alterations that differentiates attenuated from pathogenic ZIKV strains. Glycolytic rewiring results in impaired oxidative phosphorylation and mitochondrial dysfunction that trigger inflammation and apoptosis in pathogenic but not attenuated ZIKV strains. Critically, pyruvate supplementation prevents cell death, in vitro, and rescues fetal development in ZIKV-infected dams. Our findings thus demonstrate dysregulated metabolism as an underpinning of ZIKV pathogenicity and raise the potential of pyruvate supplementation in expectant women as a prophylaxis against congenital Zika syndrome.

Keywords: Zika virus; attenuated; congenital zika syndrome; glycolysis; pathogenic; pyruvate supplementation; tricarboxylic acid cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorocebus aethiops
  • Dietary Supplements
  • Female
  • Fetal Development*
  • Glycolysis*
  • Humans
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Oxidative Phosphorylation
  • Pentose Phosphate Pathway
  • Pyruvic Acid / administration & dosage
  • Vero Cells
  • Virus Replication*
  • Zika Virus / physiology*
  • Zika Virus Infection / complications*
  • Zika Virus Infection / pathology
  • Zika Virus Infection / virology


  • Pyruvic Acid