{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:15:34Z","timestamp":1791486934760,"version":"4.3.4"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,10,29]],"date-time":"2019-10-29T00:00:00Z","timestamp":1572307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to be associated with complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with induction of cell death. However, previous studies suggest that the virally induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to interfere with apoptosis whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.<\/jats:p>","DOI":"10.3390\/cells8111338","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T05:18:26Z","timestamp":1572499106000},"page":"1338","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The ZIKA Virus Delays Cell Death Through the Anti-Apoptotic Bcl-2 Family Proteins"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2667-345X","authenticated-orcid":false,"given":"Jonathan","family":"Turpin","sequence":"first","affiliation":[{"name":"PIMIT, Processus Infectieux en Milieu Insulaire Tropical, Universit\u00e9 de La R\u00e9union, INSERM UMR 1187, CNRS 9192, IRD 249, Plateforme CYROI, 97490 Sainte-Clotilde, Ile de La R\u00e9union, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Frumence","sequence":"additional","affiliation":[{"name":"PIMIT, Processus Infectieux en Milieu Insulaire Tropical, Universit\u00e9 de La R\u00e9union, INSERM UMR 1187, CNRS 9192, IRD 249, Plateforme CYROI, 97490 Sainte-Clotilde, Ile de La R\u00e9union, France"}],"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":"PIMIT, Processus Infectieux en Milieu Insulaire Tropical, Universit\u00e9 de La R\u00e9union, INSERM UMR 1187, CNRS 9192, IRD 249, Plateforme CYROI, 97490 Sainte-Clotilde, Ile de La R\u00e9union, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0915-8635","authenticated-orcid":false,"given":"Wildriss","family":"Viranaicken","sequence":"additional","affiliation":[{"name":"PIMIT, Processus Infectieux en Milieu Insulaire Tropical, Universit\u00e9 de La R\u00e9union, INSERM UMR 1187, CNRS 9192, IRD 249, Plateforme CYROI, 97490 Sainte-Clotilde, Ile de La R\u00e9union, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Krejbich-Trotot","sequence":"additional","affiliation":[{"name":"PIMIT, Processus Infectieux en Milieu Insulaire Tropical, Universit\u00e9 de La R\u00e9union, INSERM UMR 1187, CNRS 9192, IRD 249, Plateforme CYROI, 97490 Sainte-Clotilde, Ile de La R\u00e9union, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"606","DOI":"10.2105\/AJPH.2016.303112","article-title":"History, Epidemiology, and Clinical Manifestations of Zika: A Systematic Review","volume":"106","author":"Barreto","year":"2016","journal-title":"Am. J. Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/S0140-6736(16)00562-6","article-title":"Guillain-Barr\u00e9 Syndrome outbreak associated with Zika virus infection in French Polynesia: A case-control study","volume":"387","author":"Blake","year":"2016","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/S1473-3099(16)30462-5","article-title":"Zika virus and microcephaly","volume":"16","author":"Lover","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"McKenzie, B.A., Wilson, A.E., and Zohdy, S. (2019). Aedes albopictus is a competent vector of Zika virus: A meta-analysis. PLoS ONE.","DOI":"10.1371\/journal.pone.0216794"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kraemer, M.U., Sinka, M.E., Duda, K.A., Mylne, A.Q., Shearer, F.M., Barker, C.M., Moore, C.G., Carvalho, R.G., Coelho, G.E., and Van Bortel, W. (2015). The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus. eLife.","DOI":"10.7554\/eLife.08347.014"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Haddow, A.D., Schuh, A.J., Yasuda, C.Y., Kasper, M.R., Heang, V., Huy, R., Guzman, H., Tesh, R.B., and Weaver, S.C. (2012). Genetic Characterization of Zika Virus Strains: Geographic Expansion of the Asian Lineage. PLoS Negl. Trop. Dis.","DOI":"10.1371\/journal.pntd.0001477"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.apjtm.2016.03.028","article-title":"Zika Virus spreading in South America: Evolutionary analysis of emerging neutralizing resistant Phe279Ser strains","volume":"9","author":"Giovanetti","year":"2016","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.coviro.2014.09.020","article-title":"Coupling of replication and assembly in flaviviruses","volume":"9","author":"Sirohi","year":"2014","journal-title":"Curr. Opin. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8880","DOI":"10.1128\/JVI.00354-15","article-title":"Biology of Zika Virus Infection in Human Skin Cells","volume":"89","author":"Hamel","year":"2015","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1080\/21505594.2019.1605803","article-title":"The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, and HIV infections","volume":"10","author":"Mehrbod","year":"2019","journal-title":"Virulence"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1146\/annurev.micro.53.1.577","article-title":"Viruses and Apoptosis","volume":"53","author":"Roulston","year":"1999","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_12","first-page":"314","article-title":"Chikungunya virus mobilizes the apoptotic machinery to invade host cell defenses","volume":"25","author":"Denizot","year":"2011","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1080\/08830180490265529","article-title":"Alphaviruses and apoptosis","volume":"23","author":"Li","year":"2004","journal-title":"Int. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Okamoto, T., Suzuki, T., Kusakabe, S., Tokunaga, M., Hirano, J., Miyata, Y., and Matsuura, Y. (2017). Regulation of Apoptosis during Flavivirus Infection. Viruses.","DOI":"10.3390\/v9090243"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.micinf.2010.04.005","article-title":"West Nile virus capsid protein interaction with importin and HDM2 protein is regulated by protein kinase C-mediated phosphorylation","volume":"12","author":"Bhuvanakantham","year":"2010","journal-title":"Microbes Infect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1128\/JVI.02030-12","article-title":"The West Nile Virus Capsid Protein Blocks Apoptosis through a Phosphatidylinositol 3-Kinase-Dependent Mechanism","volume":"87","author":"Urbanowski","year":"2013","journal-title":"J. Virol."},{"key":"ref_17","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-\u03b2 production and apoptosis induction","volume":"493","author":"Frumence","year":"2016","journal-title":"Virology"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Limonta, D., Jovel, J., Kumar, A., Airo, A.M., Hou, S., Saito, L., Branton, W., Ka-Shu Wong, G., Mason, A., and Power, C. (2018). Human Fetal Astrocytes Infected with Zika Virus Exhibit Delayed Apoptosis and Resistance to Interferon: Implications for Persistence. Viruses.","DOI":"10.3390\/v10110646"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.15585\/mmwr.mm6547e2","article-title":"Description of 13 Infants Born During October 2015-January 2016 With Congenital Zika Virus Infection Without Microcephaly at Birth-Brazil","volume":"65","author":"Pessoa","year":"2016","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_20","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_21","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_22","doi-asserted-by":"crossref","unstructured":"Nativel, B., Marimoutou, M., Thon-Hon, V.G., Gunasekaran, M.K., Andries, J., Stanislas, G., Planesse, C., Da Silva, C.R., C\u00e9sari, M., and Iwema, T. (2013). Soluble HMGB1 is a novel adipokine stimulating IL-6 secretion through RAGE receptor in SW872 preadipocyte cell line: Contribution to chronic inflammation in fat tissue. PLoS ONE.","DOI":"10.1371\/journal.pone.0076039"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Viranaicken, W., Gasmi, L., Chaumet, A., Durieux, C., Georget, V., Denoulet, P., and Larcher, J.-C. (2011). L-Ilf3 and L-NF90 Traffic to the Nucleolus Granular Component: Alternatively-Spliced Exon 3 Encodes a Nucleolar Localization Motif. PLoS ONE.","DOI":"10.1371\/journal.pone.0022296"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0962-8924(97)01215-4","article-title":"Inhibition of TNF-induced apoptosis by NF-\u03baB","volume":"8","author":"Antwerp","year":"1998","journal-title":"Trends Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"El Kalamouni, C., Frumence, E., Bos, S., Turpin, J., Nativel, B., Harrabi, W., Wilkinson, D.A., Meilhac, O., Gadea, G., and Despr\u00e8s, P. (2018). Subversion of the Heme Oxygenase-1 Antiviral Activity by Zika Virus. Viruses, 11.","DOI":"10.3390\/v11010002"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.bbamcr.2011.01.026","article-title":"Caspase-8 and bid: Caught in the act between death receptors and mitochondria","volume":"1813","author":"Kantari","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1101\/gad.13.15.1899","article-title":"BCL-2 family members and the mitochondria in apoptosis","volume":"13","author":"Gross","year":"1999","journal-title":"Genes Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nature03579","article-title":"An inhibitor of Bcl-2 family proteins induces regression of solid tumours","volume":"435","author":"Oltersdorf","year":"2005","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1128\/CMR.00072-15","article-title":"Zika Virus","volume":"29","author":"Musso","year":"2016","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/nri.2016.147","article-title":"Programmed cell death as a defence against infection","volume":"17","author":"Jorgensen","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Souza, B.S.F., Sampaio, G.L.A., Pereira, C.S., Campos, G.S., Sardi, S.I., Freitas, L.A.R., Figueira, C.P., Paredes, B.D., Nonaka, C.K.V., and Azevedo, C.M. (2016). Zika virus infection induces mitosis abnormalities and apoptotic cell death of human neural progenitor cells. Sci. Rep.","DOI":"10.1038\/srep39775"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.stem.2016.04.017","article-title":"Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice","volume":"19","author":"Li","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2440","DOI":"10.1038\/cddis.2016.266","article-title":"ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly and p53","volume":"7","author":"Ghouzzi","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8388","DOI":"10.1128\/JVI.79.13.8388-8399.2005","article-title":"Flavivirus Activates Phosphatidylinositol 3-Kinase Signaling To Block Caspase-Dependent Apoptotic Cell Death at the Early Stage of Virus Infection","volume":"79","author":"Lee","year":"2005","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.7150\/ijbs.26400","article-title":"Zika Virus Envelope Protein induces G2\/M Cell Cycle Arrest and Apoptosis via an Intrinsic Cell Death Signaling Pathway in Neuroendocrine PC12 Cells","volume":"14","author":"Liu","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wu, Y., Liu, Q., Zhou, J., Xie, W., Chen, C., Wang, Z., Yang, H., and Cui, J. (2017). Zika virus evades interferon-mediated antiviral response through the co-operation of multiple nonstructural proteins in vitro. Cell Discov.","DOI":"10.1038\/celldisc.2017.14"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Barnard, T.R., Rajah, M.M., and Sagan, S.M. (2018). Contemporary Zika Virus Isolates Induce More dsRNA and Produce More Negative-Strand Intermediate in Human Astrocytoma Cells. Viruses.","DOI":"10.3390\/v10120728"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.virusres.2017.08.015","article-title":"Functional RNA during Zika virus infection","volume":"254","author":"Abbo","year":"2018","journal-title":"Virus Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1038\/ncb1499","article-title":"Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies","volume":"8","author":"Kim","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1182\/blood-2013-08-519470","article-title":"Antiapoptotic potency of Bcl-2 proteins primarily relies on their stability, not binding selectivity","volume":"123","author":"Rooswinkel","year":"2014","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Suzuki, T., Okamoto, T., Katoh, H., Sugiyama, Y., Kusakabe, S., Tokunaga, M., Hirano, J., Miyata, Y., Fukuhara, T., and Ikawa, M. (2018). Infection with flaviviruses requires BCLXL for cell survival. PLOS Pathog.","DOI":"10.1371\/journal.ppat.1007299"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/11\/1338\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:30:15Z","timestamp":1760189415000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/11\/1338"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,29]]},"references-count":41,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["cells8111338"],"URL":"https:\/\/doi.org\/10.3390\/cells8111338","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.736838355.793568349","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,29]]}}}