{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T23:07:53Z","timestamp":1780355273524,"version":"3.54.1"},"reference-count":51,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T00:00:00Z","timestamp":1725494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Huck Institutes of the Life Sciences, Pennsylvania State University"},{"name":"School of Public Health, University of Pittsburg"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Zika virus (ZIKV), a mosquito-borne flavivirus, is a significant global health concern due to its association with neurodevelopmental disorders such as congenital Zika syndrome (CZS). This study aimed to compare the replication kinetics, viral persistence, cytopathogenic effects, and immune gene expression in human microglia cells (CHME-3) infected with an Asian lineage ZIKV (PRVABC59, referred to as ZIKV-PRV) and an African lineage ZIKV (IBH30656, referred to as ZIKV-IBH). We found that ZIKV-PRV replicated more efficiently and persisted longer while inducing lower levels of cell death and inflammatory gene activation compared with ZIKV-IBH. These findings suggest that the enhanced replication and persistence of ZIKV-PRV, along with its ability to evade innate immune responses, may underlie its increased neuropathogenic potential, especially in the context of CZS. In contrast, ZIKV-IBH, with its stronger immune gene activation and higher cytopathogenicity, may lead to more acute infections with faster viral clearance, thereby reducing the likelihood of chronic central nervous system (CNS) infection. This study provides crucial insights into the molecular and cellular mechanisms driving the differential pathogenicity of ZIKV lineages and highlights the need for further research to pinpoint the viral factors responsible for these distinct clinical outcomes.<\/jats:p>","DOI":"10.3390\/microorganisms12091840","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T06:44:29Z","timestamp":1725518669000},"page":"1840","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Distinct Replication Kinetics, Cytopathogenicity, and Immune Gene Regulation in Human Microglia Cells Infected with Asian and African Lineages of Zika Virus"],"prefix":"10.3390","volume":"12","author":[{"given":"Ian M.","family":"Bird","sequence":"first","affiliation":[{"name":"Animal Diagnostic Laboratory, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Cavener","sequence":"additional","affiliation":[{"name":"Animal Diagnostic Laboratory, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meera","family":"Surendran Nair","sequence":"additional","affiliation":[{"name":"Animal Diagnostic Laboratory, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3102-7447","authenticated-orcid":false,"given":"Ruth H.","family":"Nissly","sequence":"additional","affiliation":[{"name":"Animal Diagnostic Laboratory, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7109-7810","authenticated-orcid":false,"given":"Shubhada K.","family":"Chothe","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshy","family":"Jacob","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh V.","family":"Kuchipudi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41594-017-0010-8","article-title":"Structural biology of Zika virus and other flaviviruses","volume":"25","author":"Hasan","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.9734\/sajrm\/2019\/v4i430115","article-title":"Emergence and Re-emergence of Zika Virus; History and Current Trend","volume":"4","author":"Ajide","year":"2019","journal-title":"South Asian J. Res. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1007\/s10096-018-3354-z","article-title":"Zika virus: Epidemiology, clinical aspects, diagnosis, and control of infection","volume":"37","author":"Karkhah","year":"2018","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s13365-018-0614-8","article-title":"Zika virus outbreak: A review of neurological complications, diagnosis, and treatment options","volume":"24","author":"Koppolu","year":"2018","journal-title":"J. NeuroVirol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1097\/01.ogx.0000489564.35748.52","article-title":"Guillain-Barr\u00e9 Syndrome Outbreak Associated with Zika Virus Infection in French Polynesia: A Case-Control Study","volume":"71","author":"Blake","year":"2016","journal-title":"Obstet. Gynecol. Surv."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mier-Y-Teran-Romero, L., Delorey, M.J., Sejvar, J.J., and Johansson, M.A. (2018). Guillain-Barr\u00e9 syndrome risk among individuals infected with Zika virus: A multi-country assessment. BMC Med., 16.","DOI":"10.1186\/s12916-018-1052-4"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"aaf8160","DOI":"10.1126\/science.aaf8160","article-title":"Assessing the global threat from Zika virus","volume":"353","author":"Lessler","year":"2016","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"242","DOI":"10.15585\/mmwr.mm6509e2","article-title":"Increase in Reported Prevalence of Microcephaly in Infants Born to Women Living in Areas with Confirmed Zika Virus Transmission During the First Trimester of Pregnancy\u2014Brazil, 2015","volume":"65","author":"Henriques","year":"2016","journal-title":"MMWR. Morb. Mortal. Wkly. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1056\/NEJMoa1600651","article-title":"Zika virus associated with microcephaly","volume":"374","author":"Mlakar","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Manangeeswaran, M., Ireland, D.D.C., and Verthelyi, D. (2016). Zika (PRVABC59) Infection Is Associated with T cell Infiltration and Neurodegeneration in CNS of Immunocompetent Neonatal C57Bl\/6 Mice. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1006004"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.bbrc.2017.01.074","article-title":"The impact of Zika virus in the brain","volume":"492","author":"Russo","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1126\/science.aaf6116","article-title":"Zika virus: Zika virus impairs growth in human neurospheres and brain organoids","volume":"352","author":"Garcez","year":"2016","journal-title":"Science"},{"key":"ref_13","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_14","doi-asserted-by":"crossref","unstructured":"Limonta, D., Jovel, J., Kumar, A., Airo, A., 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, 10.","DOI":"10.3390\/v10110646"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Goodfellow, F.T., Willard, K.A., Stice, S.L., Brindley, M.A., Wu, X., and Scoville, S. (2018). Strain-dependent consequences of zika virus infection and differential impact on neural development. Viruses, 10.","DOI":"10.3390\/v10100550"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jviromet.2016.09.015","article-title":"A sensitive virus yield assay for evaluation of Antivirals against Zika Virus","volume":"238","author":"Goebel","year":"2016","journal-title":"J. Virol. Methods"},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.chom.2016.05.015","article-title":"Zika Virus Infects Human Placental Macrophages","volume":"20","author":"Quicke","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.1038\/s41467-018-05826-w","article-title":"Early cellular innate immune responses drive Zika viral persistence and tissue tropism in pigtail macaques","volume":"9","author":"Lewis","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","unstructured":"Morrison, T.E., and Diamond, M.S. (2017). Animal Models of Zika Virus Infection, Pathogenesis, and Immunity. J. Virol., 91.","DOI":"10.1128\/JVI.00009-17"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17006","DOI":"10.1038\/celldisc.2017.6","article-title":"Zika virus evades interferon-mediated antiviral response through the co-operation of multiple nonstructural proteins in vitro","volume":"3","author":"Wu","year":"2017","journal-title":"Cell Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nature18296","article-title":"The Brazilian Zika virus strain causes birth defects in experimental models","volume":"534","author":"Cugola","year":"2016","journal-title":"Nature"},{"key":"ref_25","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_26","doi-asserted-by":"crossref","unstructured":"Rayner, J.O., Kalkeri, R., Goebel, S., Cai, Z., Green, B., Lin, S., Snyder, B., Hagelin, K., Walters, K.B., and Koide, F. (2018). Comparative Pathogenesis of Asian and African-Lineage Zika Virus in Indian Rhesus Macaque\u2019s and Development of a Non-Human Primate Model Suitable for the Evaluation of New Drugs and Vaccines. Viruses, 10.","DOI":"10.20944\/preprints201804.0096.v1"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bowen, J.R., Quicke, K.M., Maddur, M.S., O\u2019Neal, J.T., McDonald, C.E., Fedorova, N.B., Puri, V., Shabman, R.S., Pulendran, B., and Suthar, M.S. (2017). Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006164"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Vielle, N.J., Zumkehr, B., Garc\u00eda-Nicol\u00e1s, O., Blank, F., Stojanov, M., Musso, D., Baud, D., Summerfield, A., and Alves, M.P. (2018). Silent infection of human dendritic cells by African and Asian strains of Zika virus. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-23734-3"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1146\/annurev.micro.62.081307.163009","article-title":"Viral subversion of apoptotic enzymes: Escape from death row","volume":"62","author":"Best","year":"2008","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bernhauerova, V., Rezelj, V.V., and Vignuzzi, M. (2020). Modelling Degradation and Replication Kinetics of the Zika Virus In Vitro Infection. Viruses, 12.","DOI":"10.3390\/v12050547"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Turpin, J., El Safadi, D., Lebeau, G., Krejbich, M., Chatelain, C., Despres, P., Viranaicken, W., and Krejbich-Trotot, P. (2022). Apoptosis during ZIKA Virus Infection: Too Soon or Too Late?. Int. J. Mol. Sci., 23.","DOI":"10.20944\/preprints202112.0484.v1"},{"key":"ref_32","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., 14.","DOI":"10.1371\/journal.ppat.1007299"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Best, S.M. (2017). The Many Faces of the Flavivirus NS5 Protein in Antagonism of Type I Interferon Signaling. J. Virol., 91.","DOI":"10.1128\/JVI.01970-16"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s12985-016-0590-7","article-title":"Flavivirus NS1: A multifaceted enigmatic viral protein","volume":"13","author":"Rastogi","year":"2016","journal-title":"Virol. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S935","DOI":"10.1093\/infdis\/jix515","article-title":"Zika Virus Structure, Maturation, and Receptors","volume":"216","author":"Sirohi","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1165\/rcmb.2006-0283RC","article-title":"NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I","volume":"36","author":"Guo","year":"2007","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.1073\/pnas.1114981109","article-title":"Systematic identification of type I and type II interferon-induced antiviral factors","volume":"109","author":"Liu","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/sj.icb.7100100","article-title":"Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response","volume":"85","author":"Thompson","year":"2007","journal-title":"Immunol. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.virusres.2017.08.018","article-title":"Taking the defensive: Immune control of Zika virus infection","volume":"254","author":"Bowen","year":"2018","journal-title":"Virus Res."},{"key":"ref_40","first-page":"632","article-title":"Antiviral macrophage responses in flavivirus encephalitis","volume":"138","author":"Ashhurst","year":"2013","journal-title":"Indian. J. Med. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s00705-003-0238-y","article-title":"Virus spread, tissue inflammation and antiviral response in brains of flavivirus susceptible and resistant mice acutely infected with Murray Valley encephalitis virus","volume":"149","author":"Silvia","year":"2004","journal-title":"Arch. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Valad\u00e3o, A.L.C., Aguiar, R.S., and de Arruda, L.B. (2016). Interplay between inflammation and cellular stress triggered by Flaviviridae viruses. Front. Microbiol., 7.","DOI":"10.3389\/fmicb.2016.01233"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.15252\/embj.201695871","article-title":"Zika virus NS1, a pathogenicity factor with many faces","volume":"35","author":"Hilgenfeld","year":"2016","journal-title":"Embo J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1021\/acs.jcim.2c01461","article-title":"NS1 from Two Zika Virus Strains Differently Interact with a Membrane: Insights to Understand Their Differential Virulence","volume":"63","author":"Etchebest","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Yu, Y., Gao, C., Wen, C., Zou, P., Qi, X., Cardona, C.J., and Xing, Z. (2022). Intrinsic features of Zika Virus non-structural proteins NS2A and NS4A in the regulation of viral replication. PLoS Negl. Trop. Dis., 16.","DOI":"10.1371\/journal.pntd.0010366"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Collette, N.M., Lao, V.H.I., Weilhammer, D.R., Zingg, B., Cohen, S.D., Hwang, M., Coffey, L.L., Grady, S.L., Zemla, A.T., and Borucki, M.K. (2020). Single Amino Acid Mutations Affect Zika Virus Replication In Vitro and Virulence In Vivo. Viruses, 12.","DOI":"10.1101\/2020.08.06.239392"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Song, W., Zhang, H., Zhang, Y., Chen, Y., Lin, Y., Han, Y., and Jiang, J. (2021). Identification and Characterization of Zika Virus NS5 Methyltransferase Inhibitors. Front. Cell Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.665379"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lundberg, R., Mel\u00e9n, K., Westenius, V., Jiang, M., \u00d6sterlund, P., Khan, H., Vapalahti, O., Julkunen, I., and Kakkola, L. (2019). Zika Virus Non-Structural Protein NS5 Inhibits the RIG-I Pathway and Interferon Lambda 1 Promoter Activation by Targeting IKK Epsilon. Viruses, 11.","DOI":"10.3390\/v11111024"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.virusres.2014.09.011","article-title":"Human coronaviruses: Viral and cellular factors involved in neuroinvasiveness and neuropathogenesis","volume":"194","author":"Desforges","year":"2014","journal-title":"Virus Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Pettersson, J.H., Eldholm, V., Seligman, S.J., Lundkvist, \u00c5., Falconar, A.K., Gaunt, M.W., Musso, D., Nougair\u00e8de, A., Charrel, R., and Gould, E.A. (2016). How Did Zika Virus Emerge in the Pacific Islands and Latin America?. mBio, 7.","DOI":"10.1128\/mBio.01239-16"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1001\/jamaneurol.2016.0800","article-title":"Zika Virus as an Emerging Global Pathogen: Neurological Complications of Zika Virus","volume":"73","author":"Beckham","year":"2016","journal-title":"JAMA Neurol."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/12\/9\/1840\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:49:11Z","timestamp":1760111351000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/12\/9\/1840"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,5]]},"references-count":51,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["microorganisms12091840"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms12091840","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,5]]}}}