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Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved July 2, 2020 (received for review March 26, 2020)
Significance
ZIKV has “silently” circulated without causing severe diseases for decades since its discovery in 1947. Our study demonstrated that ZIKV acquired an evolutionary mutation in viral envelope gene (E-V473M) that increases virulence, maternal-to-fetal transmission during pregnancy, and viremia in nonhuman primates to facilitate urban transmission since 2013, which may be responsible for the recent emergence and severe diseases. Our results underscore the potential that high genetic mutation frequencies during arbovirus replication and transmission between mosquito and vertebrate hosts could lead to emergence and reemergence of those pathogens. Understanding the mechanisms of emergence and enhanced transmission is essential to detect and respond to future arbovirus outbreaks.
Abstract
Arboviruses maintain high mutation rates due to lack of proofreading ability of their viral polymerases, in some cases facilitating adaptive evolution and emergence. Here we show that, just before its 2013 spread to the Americas, Zika virus (ZIKV) underwent an envelope protein V473M substitution (E-V473M) that increased neurovirulence, maternal-to-fetal transmission, and viremia to facilitate urban transmission. A preepidemic Asian ZIKV strain (FSS13025 isolated in Cambodia in 2010) engineered with the V473M substitution significantly increased neurovirulence in neonatal mice and produced higher viral loads in the placenta and fetal heads in pregnant mice. Conversely, an epidemic ZIKV strain (PRVABC59 isolated in Puerto Rico in 2015) engineered with the inverse M473V substitution reversed the pathogenic phenotypes. Although E-V473M did not affect oral infection of Aedes aegypti mosquitoes, competition experiments in cynomolgus macaques showed that this mutation increased its fitness for viremia generation, suggesting adaptive evolution for human viremia and hence transmission. Mechanistically, the V473M mutation, located at the second transmembrane helix of the E protein, enhances virion morphogenesis. Overall, our study revealed E-V473M as a critical determinant for enhanced ZIKV virulence, intrauterine transmission during pregnancy, and viremia to facilitate urban transmission.
Footnotes
↵1C.S. and H.X. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: shanchao{at}wh.iov.cn, sweaver{at}UTMB.edu, or peshi{at}UTMB.edu.
Author contributions: C.S., H.X., S.L.H., S.R.A., Y.L., S.L.R., N.V., X.X., S.C.W., and P.-Y.S. designed research; C.S., H.X., S.L.H., S.R.A., Y.L., J.L., A.E.M., R.C., S.L.R., M.W., N.V., R.P., C.R.F.-G., S.K.S., and X.X. performed research; C.S., H.X., S.L.H., S.R.A., Y.L., J.L., A.E.M., R.C., S.L.R., M.W., N.V., R.P., C.R.F.-G., S.K.S., X.X., S.C.W., and P.-Y.S. analyzed data; and C.S., H.X., S.L.H., S.R.A., S.C.W., and P.-Y.S. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2005722117/-/DCSupplemental.
Data Availability.
Source data for generating main figures are available in the SI Appendix.
Published under the PNAS license.
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A Zika virus envelope mutation preceding the 2015 epidemic enhances virulence and fitness for transmission
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