Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857, Singapore.
Singapore-MIT Alliance in Research and Technology, Antimicrobial Resistance Interdisciplinary Research Group, Singapore 138602, Singapore.
Cell Rep. 2021 Dec 14;37(11):110118. doi: 10.1016/j.celrep.2021.110118.
Zika virus (ZIKV) is an Aedes-mosquito-borne flavivirus that causes debilitating congenital and developmental disorders. Improved understanding of ZIKV pathogenesis could assist efforts to fill the therapeutic and vaccine gap. We use several ZIKV strains, including a pair differing by a single phenylalanine-to-leucine substitution (M-F37L) in the membrane (M) protein, coupled with unbiased genomics to demarcate the border between attenuated and pathogenic infection. We identify infection-induced metabolic dysregulation as a minimal set of host alterations that differentiates attenuated from pathogenic ZIKV strains. Glycolytic rewiring results in impaired oxidative phosphorylation and mitochondrial dysfunction that trigger inflammation and apoptosis in pathogenic but not attenuated ZIKV strains. Critically, pyruvate supplementation prevents cell death, in vitro, and rescues fetal development in ZIKV-infected dams. Our findings thus demonstrate dysregulated metabolism as an underpinning of ZIKV pathogenicity and raise the potential of pyruvate supplementation in expectant women as a prophylaxis against congenital Zika syndrome.
Zika 病毒（ZIKV）是一种由埃及伊蚊传播的黄病毒，可导致严重的先天性和发育性疾病。深入了解 ZIKV 的发病机制有助于填补治疗和疫苗空白。我们使用了几种 ZIKV 毒株，包括一对在膜（M）蛋白中仅相差一个苯丙氨酸到亮氨酸取代（M-F37L）的毒株，同时结合无偏基因组学来划定减毒和致病感染之间的边界。我们发现感染诱导的代谢失调是区分减毒和致病性 ZIKV 毒株的宿主改变的最小集合。糖酵解重编程导致氧化磷酸化受损和线粒体功能障碍，从而引发致病性但不是减毒 ZIKV 毒株的炎症和细胞凋亡。至关重要的是，丙酮酸补充可防止细胞死亡，在体外，并挽救感染 ZIKV 的母鼠中的胎儿发育。我们的研究结果因此表明，代谢失调是 ZIKV 致病性的基础，并提出了在孕妇中补充丙酮酸作为预防先天性 Zika 综合征的潜在可能性。
