Aberrant NAD+ metabolism underlies Zika virus-induced microcephaly

ABSTRACT: 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. We perform a multi-omics study comprising transcriptomics, proteomics, phosphoproteomics, and metabolomics approaches on the brains from ZIKV-infected mice. 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 cGMP-PKG signalling may be associated with ZIKV-induced microcephaly. Importantly, we demonstrate the utility of our rich multi-omics datasets with follow-up in vivo experiments which confirm that boosting NAD+ by NAD+ or NR supplementation alleviates cell death and increases cortex thickness in ZIKV-infected mouse brains. NR 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.

ORGANISM(S): Mus Musculus

SUBMITTER: Zeping Hu  

PROVIDER: PXD026814 | iProX | Fri Jun 18 00:00:00 BST 2021

REPOSITORIES: iProX