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Aberrant NAD+ metabolism underlies Zika virus–induced microcephaly
Nature Metabolism ( IF 18.9 ) Pub Date : 2021-08-12 , DOI: 10.1038/s42255-021-00437-0
Huanhuan Pang 1 , Yisheng Jiang 2, 3 , Jie Li 1, 4 , Yushen Wang 5, 6 , Meng Nie 1 , Nan Xiao 1 , Shuo Wang 2, 3 , Zhihong Song 4 , Fansen Ji 4 , Yafei Chang 7 , Yu Zheng 2 , Ke Yao 1 , LiAng Yao 1 , Shao Li 8 , Peng Li 5, 9, 10 , Lei Song 6 , Xun Lan 4, 11 , Zhiheng Xu 2, 3, 12 , Zeping Hu 1
Affiliation  

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.



中文翻译:

NAD+ 代谢异常是寨卡病毒诱导的小头畸形的基础

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。

更新日期:2021-08-12
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