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Title: Dysregulated metabolism underpins Zika-virus-infection-associated impairment in fetal development
Authors: Yau, Clement
Low, John Z. H. 
Gan, Esther S. 
Kwek, Swee Sen
Cui, Liang
Tan, Hwee Cheng 
Mok, Darren Z. L. 
Chan, Candice Y. Y.
Sessions, October M. 
Watanabe, Satoru 
Vasudevan, Subhash G. 
Lee, Yie Hou
Chan, Kuan Rong 
Ooi, Eng Eong 
Keywords: attenuated
congenital zika syndrome
pyruvate supplementation
tricarboxylic acid cycle
Zika virus
Issue Date: 1-Dec-2021
Publisher: Elsevier B.V.
Citation: Yau, Clement, Low, John Z. H., Gan, Esther S., Kwek, Swee Sen, Cui, Liang, Tan, Hwee Cheng, Mok, Darren Z. L., Chan, Candice Y. Y., Sessions, October M., Watanabe, Satoru, Vasudevan, Subhash G., Lee, Yie Hou, Chan, Kuan Rong, Ooi, Eng Eong (2021-12-01). Dysregulated metabolism underpins Zika-virus-infection-associated impairment in fetal development. Cell Reports 37 (11) : 110118. ScholarBank@NUS Repository.
Rights: Attribution-NonCommercial-NoDerivatives 4.0 International
Abstract: 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. © 2021 The Authors
Source Title: Cell Reports
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2021.110118
Rights: Attribution-NonCommercial-NoDerivatives 4.0 International
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