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A Zika virus envelope mutation preceding the 2015 epidemic
enhances virulence and fitness for transmission, , , , , , , , , , , , , , , , ,
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.
REFERENCE:
Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):20190-20197. doi: 10.1073/pnas.2005722117. Epub 2020 Aug 3.
, , , , , , , , , , , , , , , ,
Affiliations
1 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555; shanchao@wh.iov.cn sweaver@UTMB.edu peshi@UTMB.edu.
2 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071 Wuhan, China.
3 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555.
4 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
5 Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555.
6 Institute for Translational Science, University of Texas Medical Branch, Galveston, TX 77555.
7 Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555.
8 World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX 77555.
9 Center for Biodefence and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555.
10 Center for Tropical Diseases, University of Texas Medical Branch, Galveston, TX 77555.
11 Department of Neurosurgery-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
12 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555; shanchao@wh.iov.cn sweaver@UTMB.edu peshi@UTMB.edu.
13 Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX 77555.
14 Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555.
PMID: 32747564 PMCID: PMC7443865 DOI: 10.1073/pnas.2005722117
Affiliations
1 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555; shanchao@wh.iov.cn sweaver@UTMB.edu peshi@UTMB.edu.
2 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071 Wuhan, China.
3 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555.
4 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
5 Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555.
6 Institute for Translational Science, University of Texas Medical Branch, Galveston, TX 77555.
7 Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555.
8 World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX 77555.
9 Center for Biodefence and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555.
10 Center for Tropical Diseases, University of Texas Medical Branch, Galveston, TX 77555.
11 Department of Neurosurgery-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
12 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555; shanchao@wh.iov.cn sweaver@UTMB.edu peshi@UTMB.edu.
13 Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX 77555.
14 Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555.
PMID: 32747564 PMCID: PMC7443865 DOI: 10.1073/pnas.2005722117
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