Aberrant NAD+ metabolism underlies Zika virus–induced microcephaly

Huanhuan Pang, Yisheng Jiang, Jie Li, Yushen Wang, Meng Nie, Nan Xiao, Shuo Wang, Zhihong Song, Fansen Ji, Yafei Chang, Yu Zheng, Ke Yao, Li Ang Yao, Shao Li, Peng Li, Lei Song, Xun Lan, Zhiheng Xu, Zeping Hu

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Zika virus (ZIKV) infection during pregnancy can cause microcephaly in newborns, yet the underlying mechanisms remain largely unexplored. Here, we reveal extensive and large-scale metabolic reprogramming events in ZIKV-infected mouse brains by performing a multi-omics study comprising transcriptomics, proteomics, phosphoproteomics and metabolomics approaches. Our proteomics and metabolomics analyses uncover dramatic alteration of nicotinamide adenine dinucleotide (NAD+)-related metabolic pathways, including oxidative phosphorylation, TCA cycle and tryptophan metabolism. Phosphoproteomics analysis indicates that MAPK and cyclic GMP–protein kinase G signaling may be associated with ZIKV-induced microcephaly. Notably, we demonstrate the utility of our rich multi-omics datasets with follow-up in vivo experiments, which confirm that boosting NAD+ by NAD+ or nicotinamide riboside supplementation alleviates cell death and increases cortex thickness in ZIKV-infected mouse brains. Nicotinamide riboside supplementation increases the brain and body weight as well as improves the survival in ZIKV-infected mice. Our study provides a comprehensive resource of biological data to support future investigations of ZIKV-induced microcephaly and demonstrates that metabolic alterations can be potentially exploited for developing therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)1109-1124
Number of pages16
JournalNature Metabolism
Volume3
Issue number8
DOIs
StatePublished - Aug 2021
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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