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A Zika Virus Envelope Mutation Preceding the 2015 Epidemic Enhances Virulence and Fitness for Transmission

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A Zika Virus Envelope Mutation Preceding the 2015 Epidemic Enhances Virulence and Fitness for Transmission A Zika virus envelope mutation preceding the 2015 epidemic enhances virulence and fitness for transmission Chao Shana,b,1,2, Hongjie Xiaa,1, Sherry L. Hallerc,d,e, Sasha R. Azarc,d,e, Yang Liua, Jianying Liuc,d, Antonio E. Muruatoc, Rubing Chenc,d,e,f, Shannan L. Rossic,d,f, Maki Wakamiyaa, Nikos Vasilakisd,f,g,h,i, Rongjuan Peib, Camila R. Fontes-Garfiasa, Sanjay Kumar Singhj, Xuping Xiea, Scott C. Weaverc,d,e,k,l,2, and Pei-Yong Shia,d,e,k,l,2 aDepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555; bState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071 Wuhan, China; cDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555; dInstitute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555; eInstitute for Translational Science, University of Texas Medical Branch, Galveston, TX 77555; fDepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555; gWorld Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX 77555; hCenter for Biodefence and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555; iCenter for Tropical Diseases, University of Texas Medical Branch, Galveston, TX 77555; jDepartment of Neurosurgery-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; kSealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX 77555; and lSealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555 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) Arboviruses maintain high mutation rates due to lack of proof- recently been shown to orchestrate flavivirus assembly through reading ability of their viral polymerases, in some cases facilitating recruiting structural proteins and viral RNA (8, 9). adaptive evolution and emergence. Here we show that, just One hypothesis for the sudden and dramatic emergence of before its 2013 spread to the Americas, Zika virus (ZIKV) under- ZIKV is that genetic changes enhanced transmission and more went an envelope protein V473M substitution (E-V473M) that in- severe diseases (10). The timing of the massive emergence in creased neurovirulence, maternal-to-fetal transmission, and 2015 correlates with the acquisition of seven amino acid changes MICROBIOLOGY viremia to facilitate urban transmission. A preepidemic Asian ZIKV in the Asian lineage ZIKV strains from 2010 to 2013 (Fig. 1 A strain (FSS13025 isolated in Cambodia in 2010) engineered with and B): C-T106A, prM-V1A, prM-S17N, E-V473M, NS1- the V473M substitution significantly increased neurovirulence in A188V, NS5-M114V, and NS5-M872V. Among the seven mu- neonatal mice and produced higher viral loads in the placenta and tations, two have been functionally analyzed. (1) Mutation NS1- fetal heads in pregnant mice. Conversely, an epidemic ZIKV strain A188V was shown to slightly enhance the infectivity of ZIKV in (PRVABC59 isolated in Puerto Rico in 2015) engineered with the inverse M473V substitution reversed the pathogenic phenotypes. laboratory Aedes aegypti mosquitoes as well as to suppress type I Although E-V473M did not affect oral infection of Aedes aegypti IFN production in mammals (11, 12). (2) Conflicting results were mosquitoes, competition experiments in cynomolgus macaques reported for mutation prM-S17N such that when engineered into showed that this mutation increased its fitness for viremia gener- ation, suggesting adaptive evolution for human viremia and hence Significance transmission. Mechanistically, the V473M mutation, located at the second transmembrane helix of the E protein, enhances virion mor- ZIKV has “silently” circulated without causing severe diseases phogenesis. Overall, our study revealed E-V473M as a critical deter- for decades since its discovery in 1947. Our study demonstrated minant for enhanced ZIKV virulence, intrauterine transmission that ZIKV acquired an evolutionary mutation in viral envelope during pregnancy, and viremia to facilitate urban transmission. gene (E-V473M) that increases virulence, maternal-to-fetal transmission during pregnancy, and viremia in nonhuman pri- Zika | envelope | evolution | transmission mates to facilitate urban transmission since 2013, which may be responsible for the recent emergence and severe diseases. fter its discovery in 1947 (1), Zika virus (ZIKV) “silently” Our results underscore the potential that high genetic muta- Acirculated in Africa and Asia between primates and mos- tion frequencies during arbovirus replication and transmission quitoes in forests with no major outbreaks and only 14 docu- between mosquito and vertebrate hosts could lead to emer- mented human infections in 60 y (2). Since 2007, ZIKV strains gence and reemergence of those pathogens. Understanding from an Asian lineage that spread from Africa decades earlier the mechanisms of emergence and enhanced transmission is have emerged to cause outbreaks and severe diseases: The first essential to detect and respond to future arbovirus outbreaks. outbreak occurred on Yap Island in 2007, followed by a large 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. outbreak in French Polynesia in 2013–2014, and finally massive 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., epidemics in the Americas from 2015–2016. The most devas- 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 tating diseases associated with the recent ZIKV epidemics C.S., H.X., S.L.H., S.R.A., S.C.W., and P.-Y.S. wrote the paper. comprise congenital Zika syndrome (CZS) in fetuses of infected The authors declare no competing interest. pregnant women and Guillain-Barré syndrome in adults (3–5). This article is a PNAS Direct Submission. Like other flaviviruses, the ZIKV genome (Fig. 1A) encodes Published under the PNAS license. three structural proteins (capsid [C], premembrane/membrane 1C.S. and H.X. contributed equally to this work. [prM], and envelope [E]) and seven nonstructural proteins (NS1, 2To whom correspondence may be addressed. Email: [email protected], sweaver@ NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The structural UTMB.edu, or [email protected]. proteins form virions that contain genomic RNA. The non- This article contains supporting information online at https://www.pnas.org/lookup/suppl/ structural proteins participate in viral replication, virion assem- doi:10.1073/pnas.2005722117/-/DCSupplemental. bly, and evasion of host immunity (6, 7). The NS2A protein has www.pnas.org/cgi/doi/10.1073/pnas.2005722117 PNAS Latest Articles | 1of8 Downloaded by guest on September 26, 2021 Fig. 1. The effect of E-V473M mutation on neurovirulence. (A) Evolutionary mutations among ZIKV strains from the Asian and African lineages. The year of isolation is indicated for each strain. Conserved amino acid changes are labeled using the FSS13025 strain as a reference. Strains FSS13025 and PRVABC59, representing preepidemic and epidemic isolates, are colored in yellow and red, respectively. (B) Phylogenetic analysis. Individual mutations from A are colored and indicated at branch points of the phylogenetic tree. To construct a phylogenetic tree, the complete open reading frame (ORF) nucleotide sequencesof73 representative ZIKV strains were aligned and analyzed using the maximum likelihood method with 1,000 bootstrap replicates using the MEGA X program. ZIKV strains are labeled by GenBank accession number, followed by strain name, country, and year of collection. (C) Neurovirulence of ZIKVs with single amino acid mutation. One-day-old CD-1 pups were infected with 1,000 PFU of FSS13025, C-T106A, prM-V1A, prM-S17N, E-V473M, NS1-A188V, NS5-M114V, or NS5-M872V virus via the intracranial route (n = 10 per group). All mutations were engineered into the preepidemic FSS13025 in SI Appendix, Fig. S1. The pups were monitored for morbidity and mortality. Survival curves are presented. Epidemic strain PRVABC59 and phosphate buffered saline (PBS) were included as a positive and negative control, respectively. E-V473M, NS5-M872V, and C-T106A mutants exhibited the highest neurovirulence among the tested viruses. Log- rank test was performed for statistical analysis. ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05, P > 0.5 nonsignificant (n.s.). The statistical analysis was performed in reference to FSS13025. (D) Brain viral loads from the FSS13025- and E-V473M–infected pups. Pups from A were sacrificed and measured for brain viral loads at indicated days postinfection. Two-way ANOVA was performed for statistical analysis. ****P < 0.0001. (E) Neurovirulence of reverse mutation E-M473V in epidemic strain PRVABC59. Log-rank test was performed for statistical analysis. ****P < 0.0001. (F) Brain viral loads from PRVABC59- and E-M473V–infected pups. The experimental procedures in E and F were identical to C and D, respectively. Two-way ANOVA was performed for statistical analysis. ****P < 0.0001. (G) Replication kinetics of FSS13025, E-V473M, PRVABC59, and E-M473V on embryonic stem H9 cells. The H9 cells were infected with indicated viruses at an MOI of 0.5. Plaque assay was performed
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