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Dysregulated Metabolism Underpins Zika Virus Infection-Associated Impairment in Fetal Development

42 Pages Posted: 20 Jul 2021 Publication Status: Published

See all articles by Clement Yau

Clement Yau

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

John Z.H. Low

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Esther Gan

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Swee Sen Kwek

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Liang Cui

Singapore-MIT Alliance for Research and Technology - Antimicrobial Resistance Interdisciplinary Research Group

Hwee-Cheng Tan

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Darren Mok

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Candice Y. Chan

Singapore General Hospital - Department of Infectious Diseases

October Sessions

National University of Singapore (NUS) - Saw Swee Hock School of Public Health

Satoru Watanabe

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Subhash G. Vasudevan

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Yie Hou Lee

Singapore-MIT Alliance in Research and Technology - Critical Analytics for Manufacturing Personalized-Medicine;

Chan Rong

National University of Singapore (NUS) - Programme in Emerging Infectious Diseases

Eng Eong Ooi

Duke-NUS Graduate Medical School - Programme in Emerging Infectious Diseases

More...

Abstract

Zika virus (ZIKV) is an Aedes mosquito-borne flavivirus that causes debilitating congenital and developmental disorders. No licensed ZIKV vaccine or treatment exist, due largely to an incomplete understanding of ZIKV pathogenesis. In this study, we used a panel of ZIKV strains, including a pair that differ by just a single amino acid substitution (phenylalanine to leucine substitution, M-F37L) in the membrane (M) protein, and coupled these with unbiased whole genome gene expression studies to demarcate the border between attenuated and pathogenic infection. We identified infection-induced metabolic dysregulation as a minimal set of host alterations that differentiated attenuated from pathogenic ZIKV strains. Glycolytic rewiring reduced availability of tricarboxylic acid (TCA) cycle substrates, resulting in impaired oxidative phosphorylation and mitochondrial dysfunction that triggered inflammation and apoptosis in pathogenic but not attenuated ZIKV strains. Exogenous supplementation of pyruvate and glutamine that feed directly into the TCA cycle, reduced inflammatory and apoptotic responses induced by wild-type ZIKV infection. Critically, pyruvate supplementation to ZIKV-infected dams prevented gross fetal developmental abnormalities and rescued fetal growth. Our findings thus pinpoint dysregulated metabolism as an underpinning of ZIKV pathogenicity and that pyruvate supplementation to expectant women could be explored as a prophylaxis for congenital Zika syndrome.

Suggested Citation

Yau, Clement and Low, John Z.H. and Gan, Esther and Kwek, Swee Sen and Cui, Liang and Tan, Hwee-Cheng and Mok, Darren and Chan, Candice Y. and Sessions, October and Watanabe, Satoru and Vasudevan, Subhash G. and Lee, Yie Hou and Rong, Chan and Ooi, Eng Eong, Dysregulated Metabolism Underpins Zika Virus Infection-Associated Impairment in Fetal Development. Available at SSRN: https://ssrn.com/abstract=3890378 or http://dx.doi.org/10.2139/ssrn.3890378
This version of the paper has not been formally peer reviewed.

Clement Yau

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

8 College Road
Singapore, 169857
Singapore

John Z.H. Low

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Singapore

Esther Gan

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Swee Sen Kwek

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

8 College Road
Singapore, 169857
Singapore

Liang Cui

Singapore-MIT Alliance for Research and Technology - Antimicrobial Resistance Interdisciplinary Research Group

Singapore

Hwee-Cheng Tan

Duke-NUS Medical School - Programme in Emerging Infectious Diseases ( email )

8 College Road
Singapore

Darren Mok

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Candice Y. Chan

Singapore General Hospital - Department of Infectious Diseases

Singapore, 169608
Singapore

October Sessions

National University of Singapore (NUS) - Saw Swee Hock School of Public Health ( email )

16 Medical Drive
#10-01
117597
Singapore

Satoru Watanabe

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

8 College Road
Singapore, 169857
Singapore

Subhash G. Vasudevan

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

8 College Road
Singapore, 169857
Singapore

Yie Hou Lee

Singapore-MIT Alliance in Research and Technology - Critical Analytics for Manufacturing Personalized-Medicine; ( email )

1Create way
Singapore
Singapore

Chan Rong

National University of Singapore (NUS) - Programme in Emerging Infectious Diseases ( email )

Singapore

Eng Eong Ooi (Contact Author)

Duke-NUS Graduate Medical School - Programme in Emerging Infectious Diseases ( email )

Singapore

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