{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:07:24Z","timestamp":1790690844004,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T00:00:00Z","timestamp":1550102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI129369"],"award-info":[{"award-number":["AI129369"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The Zika virus (ZIKV) was first isolated in Africa in 1947. It was shown to be a mild virus that had limited threat to humans. However, the resurgence of the ZIKV in the most recent Brazil outbreak surprised us because it causes severe human congenital and neurologic disorders including microcephaly in newborns and Guillain-Barr\u00e9 syndrome in adults. Studies showed that the epidemic ZIKV strains are phenotypically different from the historic strains, suggesting that the epidemic ZIKV has acquired mutations associated with the altered viral pathogenicity. However, what genetic changes are responsible for the changed viral pathogenicity remains largely unknown. One of our early studies suggested that the ZIKV structural proteins contribute in part to the observed virologic differences. The objectives of this study were to compare the historic African MR766 ZIKV strain with two epidemic Brazilian strains (BR15 and ICD) for their abilities to initiate viral infection and to confer neurocytopathic effects in the human brain\u2019s SNB-19 glial cells, and further to determine which part of the ZIKV structural proteins are responsible for the observed differences. Our results show that the historic African (MR766) and epidemic Brazilian (BR15 and ICD) ZIKV strains are different in viral attachment to host neuronal cells, viral permissiveness and replication, as well as in the induction of cytopathic effects. The analysis of chimeric viruses, generated between the MR766 and BR15 molecular clones, suggests that the ZIKV E protein correlates with the viral attachment, and the C-prM region contributes to the permissiveness and ZIKV-induced cytopathic effects. The expression of adenoviruses, expressing prM and its processed protein products, shows that the prM protein and its cleaved Pr product, but not the mature M protein, induces apoptotic cell death in the SNB-19 cells. We found that the Pr region, which resides on the N-terminal side of prM protein, is responsible for prM-induced apoptotic cell death. Mutational analysis further identified four amino-acid residues that have an impact on the ability of prM to induce apoptosis. Together, the results of this study show that the difference of ZIKV-mediated viral pathogenicity, between the historic and epidemic strains, contributed in part the functions of the structural prM-E proteins.<\/jats:p>","DOI":"10.3390\/v11020157","type":"journal-article","created":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T11:54:13Z","timestamp":1550145253000},"page":"157","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["The Roles of prM-E Proteins in Historical and Epidemic Zika Virus-mediated Infection and Neurocytotoxicity"],"prefix":"10.3390","volume":"11","author":[{"given":"Ge","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5036-0336","authenticated-orcid":false,"given":"Sandra","family":"Bos","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, Universit\u00e9 de La R\u00e9union, INSERM U1187, CNRS UMR 9192, IRD UMR 249, Sainte-Clotilde, 97400 La R\u00e9union, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin A.","family":"Tsetsarkin","sequence":"additional","affiliation":[{"name":"Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Pletnev","sequence":"additional","affiliation":[{"name":"Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8926-4050","authenticated-orcid":false,"given":"Philippe","family":"Despr\u00e8s","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, Universit\u00e9 de La R\u00e9union, INSERM U1187, CNRS UMR 9192, IRD UMR 249, Sainte-Clotilde, 97400 La R\u00e9union, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6325-4866","authenticated-orcid":false,"given":"Gilles","family":"Gadea","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte Processus Infectieux en Milieu Insulaire Tropical, Plateforme Technologique CYROI, Universit\u00e9 de La R\u00e9union, INSERM U1187, CNRS UMR 9192, IRD UMR 249, Sainte-Clotilde, 97400 La R\u00e9union, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard Y.","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Department of Microbiology-Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Institute of Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/S0140-6736(16)00273-7","article-title":"Microcephaly in Brazil: How to interpret reported numbers?","volume":"387","author":"Victora","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1001\/jamaneurol.2016.3720","article-title":"Congenital Zika Virus Infection: Beyond Neonatal Microcephaly","volume":"73","author":"Melo","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1002\/ajmg.a.38170","article-title":"The phenotypic spectrum of congenital Zika syndrome","volume":"173","author":"Feitosa","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mlakar, J., Korva, M., Tul, N., Popovic, M., Poljsak-Prijatelj, M., Mraz, J., Kolenc, M., Resman Rus, K., Vesnaver Vipotnik, T., and Fabjan Vodusek, V. (2016). Zika Virus Associated with Microcephaly. N. Engl. J. Med.","DOI":"10.1056\/NEJMoa1600651"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Driggers, R.W., Ho, C.Y., Korhonen, E.M., Kuivanen, S., Jaaskelainen, A.J., Smura, T., Rosenberg, A., Hill, D.A., DeBiasi, R.L., and Vezina, G. (2016). Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities. N. Engl. J. Med.","DOI":"10.1056\/NEJMoa1601824"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.cell.2016.04.032","article-title":"Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure","volume":"165","author":"Qian","year":"2016","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/0035-9203(52)90043-6","article-title":"Zika virus. II. Pathogenicity and physical properties","volume":"46","author":"Dick","year":"1952","journal-title":"Trans. R Soc. Trop. Med. Hyg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/BF01249709","article-title":"Zika virus infection of the central nervous system of mice","volume":"35","author":"Bell","year":"1971","journal-title":"Arch. Gesamte. Virusforsch."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/0035-9203(52)90042-4","article-title":"Zika virus. I. Isolations and serological specificity","volume":"46","author":"Dick","year":"1952","journal-title":"Trans. R Soc. Trop Med. Hyg."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lee, I., Bos, S., Li, G., Wang, S., Gadea, G., Despres, P., and Zhao, R.Y. (2018). Probing Molecular Insights into Zika Virus(-)Host Interactions. Viruses, 10.","DOI":"10.20944\/preprints201804.0063.v1"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Musso, D., Nhan, T., Robin, E., Roche, C., Bierlaire, D., Zisou, K., Shan Yan, A., Cao-Lormeau, V.M., and Broult, J. (2014). Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro. Surveill., 19.","DOI":"10.2807\/1560-7917.ES2014.19.14.20761"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1056\/NEJMoa0805715","article-title":"Zika virus outbreak on Yap Island, Federated States of Micronesia","volume":"360","author":"Duffy","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"55","DOI":"10.15585\/mmwr.mm6503e1","article-title":"Zika Virus Spreads to New Areas-Region of the Americas, May 2015-January 2016","volume":"65","author":"Hennessey","year":"2016","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1017\/S0950268818000419","article-title":"Zika virus epidemiology: From Uganda to world pandemic, an update","volume":"146","year":"2018","journal-title":"Epidemiol. Infect."},{"key":"ref_15","first-page":"E376","article-title":"Characterization of cytopathic factors through genome-wide analysis of the Zika viral proteins in fission yeast","volume":"114","author":"Li","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1146\/annurev.mi.44.100190.003245","article-title":"Flavivirus genome organization, expression, and replication","volume":"44","author":"Chambers","year":"1990","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/0470058005.ch3","article-title":"Molecular biology of flaviviruses","volume":"277","author":"Harris","year":"2006","journal-title":"Novartis. Found. Symp."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1126\/science.1153264","article-title":"Structure of the immature dengue virus at low pH primes proteolytic maturation","volume":"319","author":"Yu","year":"2008","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mecharles, S., Herrmann, C., Poullain, P., Tran, T.H., Deschamps, N., Mathon, G., Landais, A., Breurec, S., and Lannuzel, A. (2016). Acute myelitis due to Zika virus infection. Lancet.","DOI":"10.1016\/S0140-6736(16)00644-9"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Faye, O., Freire, C.C., Iamarino, A., Faye, O., de Oliveira, J.V., Diallo, M., Zanotto, P.M., and Sall, A.A. (2014). Molecular evolution of Zika virus during its emergence in the 20(th) century. PLoS Negl. Trop Dis., 8.","DOI":"10.1371\/journal.pntd.0002636"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1016\/j.celrep.2017.10.016","article-title":"Functional Analysis of Glycosylation of Zika Virus Envelope Protein","volume":"21","author":"Shan","year":"2017","journal-title":"Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.virol.2010.02.008","article-title":"A flavivirus signal peptide balances the catalytic activity of two proteases and thereby facilitates virus morphogenesis","volume":"401","author":"Lobigs","year":"2010","journal-title":"Virology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3794","DOI":"10.1128\/jvi.68.6.3794-3802.1994","article-title":"NS2B-3 proteinase-mediated processing in the yellow fever virus structural region: In vitro and in vivo studies","volume":"68","author":"Amberg","year":"1994","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1099\/vir.0.18723-0","article-title":"Cleavage of protein prM is necessary for infection of BHK-21 cells by tick-borne encephalitis virus","volume":"84","author":"Elshuber","year":"2003","journal-title":"J. Gen. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Anfasa, F., Siegers, J.Y., van der Kroeg, M., Mumtaz, N., Stalin Raj, V., de Vrij, F.M.S., Widagdo, W., Gabriel, G., Salinas, S., and Simonin, Y. (2017). Phenotypic Differences between Asian and African Lineage Zika Viruses in Human Neural Progenitor Cells. mSphere, 2.","DOI":"10.1128\/mSphere.00292-17"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jcv.2016.09.012","article-title":"An updated review of Zika virus","volume":"84","author":"Abushouk","year":"2016","journal-title":"J. Clin. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Simonin, Y., van Riel, D., Van de Perre, P., Rockx, B., and Salinas, S. (2017). Differential virulence between Asian and African lineages of Zika virus. PLoS Negl. Trop Dis., 11.","DOI":"10.1371\/journal.pntd.0005821"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.3389\/fimmu.2018.01640","article-title":"Evolution of Two Major Zika Virus Lineages: Implications for Pathology, Immune Response, and Vaccine Development","volume":"9","author":"Beaver","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.meegid.2017.03.012","article-title":"Comparative analysis of protein evolution in the genome of pre-epidemic and epidemic Zika virus","volume":"51","author":"Ramaiah","year":"2017","journal-title":"Infect. Genet. Evol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.virol.2017.12.003","article-title":"The structural proteins of epidemic and historical strains of Zika virus differ in their ability to initiate viral infection in human host cells","volume":"516","author":"Bos","year":"2018","journal-title":"Virology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1126\/science.aam7120","article-title":"A single mutation in the prM protein of Zika virus contributes to fetal microcephaly","volume":"358","author":"Yuan","year":"2017","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.stem.2016.02.016","article-title":"Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth","volume":"18","author":"Tang","year":"2016","journal-title":"Cell Stem. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.virol.2016.07.015","article-title":"A robust method for the rapid generation of recombinant Zika virus expressing the GFP reporter gene","volume":"497","author":"Gadea","year":"2016","journal-title":"Virology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1126\/science.aaf5036","article-title":"Zika virus in the Americas: Early epidemiological and genetic findings","volume":"352","author":"Faria","year":"2016","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Widman, D.G., Young, E., Yount, B.L., Plante, K.S., Gallichotte, E.N., Carbaugh, D.L., Peck, K.M., Plante, J., Swanstrom, J., and Heise, M.T. (2017). A Reverse Genetics Platform That Spans the Zika Virus Family Tree. MBio, 8.","DOI":"10.1128\/mBio.02014-16"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tsetsarkin, K.A., Kenney, H., Chen, R., Liu, G., Manukyan, H., Whitehead, S.S., Laassri, M., Chumakov, K., and Pletnev, A.G. (2016). A Full-Length Infectious cDNA Clone of Zika Virus from the 2015 Epidemic in Brazil as a Genetic Platform for Studies of Virus-Host Interactions and Vaccine Development. MBio, 7.","DOI":"10.1128\/mBio.01114-16"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jviromet.2016.07.014","article-title":"Detection of Zika virus by SYBR green one-step real-time RT-PCR","volume":"236","author":"Xu","year":"2016","journal-title":"J. Virol. Methods"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.virol.2016.03.006","article-title":"The South Pacific epidemic strain of Zika virus replicates efficiently in human epithelial A549 cells leading to IFN-beta production and apoptosis induction","volume":"493","author":"Frumence","year":"2016","journal-title":"Virology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1128\/AEM.01150-08","article-title":"Application of PCR-based methods to assess the infectivity of enteric viruses in environmental samples","volume":"75","author":"Rodriguez","year":"2009","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Zheng, A., Umashankar, M., and Kielian, M. (2010). In vitro and in vivo studies identify important features of dengue virus pr-E protein interactions. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001157"},{"key":"ref_42","first-page":"4114","article-title":"The African Zika virus MR-766 is more virulent and causes more severe brain damage than current Asian lineage and dengue virus","volume":"144","author":"Shao","year":"2017","journal-title":"Development"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.ebiom.2016.09.020","article-title":"Zika Virus Strains Potentially Display Different Infectious Profiles in Human Neural Cells","volume":"12","author":"Simonin","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.stemcr.2017.01.008","article-title":"Differential Responses of Human Fetal Brain Neural Stem Cells to Zika Virus Infection","volume":"8","author":"McGrath","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.chom.2016.05.004","article-title":"An Infectious cDNA Clone of Zika Virus to Study Viral Virulence, Mosquito Transmission, and Antiviral Inhibitors","volume":"19","author":"Shan","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8475","DOI":"10.1128\/jvi.71.11.8475-8481.1997","article-title":"Proteolytic activation of tick-borne encephalitis virus by furin","volume":"71","author":"Stadler","year":"1997","journal-title":"J. Virol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/2\/157\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:32:03Z","timestamp":1760185923000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/2\/157"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,14]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["v11020157"],"URL":"https:\/\/doi.org\/10.3390\/v11020157","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,14]]}}}