16 Dec Zika: Single Amino Acid May Lead to Virulent Outcomes
MedicalResearch.com Interview with:
Professor Ooi Eng Eong
Programme in Emerging Infectious Diseases
Duke-NUS Medical School
Professor, Saw Swee Hock School of Public Health
National University of Singapore
Co-director, Viral Research And Experimental Medicine Centre
MedicalResearch.com: What is the background for this study?
Response: The emergence of Zika virus as a cause of fetal developmental disorder, or congenital Zika syndrome (CZS), mirrors the impact of congenital rubella syndrome on public health. Congenital rubella syndrome was controlled through the development of a live attenuated rubella virus vaccine that, when given to young children, elicited long-lasting immunity that protected against rubella well into adulthood.
Indeed, live viral vaccines cause subclinical infection to elicit immunity that approaches those that develop following wild-type viral infection. However, the boundary between attenuated and virulent Zika virus has not been clearly defined, making development of any live attenuated Zika virus vaccine risky.
MedicalResearch.com: What are the main findings?
Response: We thus took advantage of a serendipitous discovery of a single amino acid substation in the M protein of Zika virus that turned a partially attenuated Zika virus into a virulent strain in a mouse model. Our investigation into the host response to infection with this pair of Zika virus strains, that differed only by this single amino acid, identified dysregulation in glycolysis and the tricarcboxylic acid (TCA) cycle as a trigger of inflammation and cell death.
Virulent Zika viruses channelled the products of glycolysis into the pentose phosphate pathway, likely to generate more nucleotides for viral genome synthesis. With reduced glycolysis, less pyruvate is available to feed into the TCA cycle that result in mitochondrial stress, inflammatory response and cell death. This detrimental cascade of processes could be inhibited by pyruvate supplementation, which reduced cell death and rescued fetal development in the mouse model.
MedicalResearch.com: What should readers take away from your report?
Response: As ethyl pyruvate is a component of many off-the-shelf nutritional supplement, our findings raise the possibility that pyruvate supplementation could be an approach to preventing CZS.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Our study was conducted in a small animal model of Zika virus infection. For clinical translation, it would be useful to determine the pharmacokinetics of ethyl pyruvate and the dose needed for useful efficacy in preventing fetal developmental abnormalities in non-human primate models.
Disclosures: Authors Swee Sen Kwek and Eng Eong Ooi are patent holders of a strain of attenuated Zika virus.
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
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