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.

怀孕期间感染寨卡病毒 (ZIKV) 可导致新生儿出现小头畸形，但其潜在机制在很大程度上仍未探索。在这里，我们通过执行包括转录组学、蛋白质组学、磷酸化蛋白质组学和代谢组学方法的多组学研究，揭示了 ZIKV 感染的小鼠大脑中广泛和大规模的代谢重编程事件。我们的蛋白质组学和代谢组学分析揭示了烟酰胺腺嘌呤二核苷酸（NAD ⁺) 相关的代谢途径，包括氧化磷酸化、TCA 循环和色氨酸代谢。磷酸蛋白质组学分析表明 MAPK 和环状 GMP-蛋白激酶 G 信号可能与 ZIKV 诱导的小头畸形有关。值得注意的是，我们通过后续体内实验证明了我们丰富的多组学数据集的实用性，这证实了通过 NAD ^{+提高 NAD +}或烟酰胺核苷补充剂可减轻 ZIKV 感染小鼠大脑的细胞死亡并增加皮层厚度。烟酰胺核苷补充剂可增加大脑和体重，并提高 ZIKV 感染小鼠的存活率。我们的研究提供了全面的生物学数据资源，以支持未来对 ZIKV 诱导的小头畸形的研究，并证明代谢改变可以潜在地用于开发治疗策略。