Aberrant NAD+ metabolism underlies Zika virus–induced microcephaly

• DOI: 10.1038/s42255-021-00437-0
• Publication Date: 2021-08-12T16:04:14Z
• Authors: Huanhuan Pang; Yisheng Jiang; Jie Li; Yushen Wang; Meng Nie; Nan Xiao; Shuo Wang; Zhihong Song; Fansen Ji; Yafei Chang; Yu Zheng; Ke Yao; LiAng Yao; Shao Li; Peng Li; Lei Song; Xun Lan; Zhiheng Xu; Zeping Hu
• Keywords: Neurons; Proteomics; 0301 basic medicine; Zika Virus Infection; Brain; Zika Virus; NAD; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Pregnancy; Tandem Mass Spectrometry; Microcephaly; Animals; Metabolomics; Female; Disease Susceptibility; Cells, Cultured; Chromatography, Liquid

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.