{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T16:10:01Z","timestamp":1792253401550,"version":"4.4.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Zika is a member of the <jats:italic>Flaviviridae<\/jats:italic> virus family that poses some of the most significant global health risks, causing neurologic complications that range from sensory neuropathy and seizures to congenital Zika syndrome (microcephaly) in infants born to mothers infected during pregnancy. The recent outbreak of Zika virus (ZIKV) and its serious health threats calls for the characterization and understanding of Zika pathogenesis, as well as host antiviral immune functions. Although ZIKV has been associated with activating the RNA interference (RNAi) immune pathway and altering host metabolism, in-depth studies are still required to uncover the specifics of the complex host-virus interactions and provide additional insights into the molecular components that determine the outcome of this disease. Previous research establishes the fruit fly <jats:italic>Drosophila melanogaster<\/jats:italic> as a reliable model for studying viral pathogens, as it shares significant similarities with that of vertebrate animal systems. Here, we have developed an <jats:italic>in vivo Drosophila<\/jats:italic> model to investigate ZIKV-mediated perturbed metabolism in correlation to the RNAi central mediator Dicer-2. We report that ZIKV infection reprograms glucose and glycogen metabolism in <jats:italic>Dicer-2<\/jats:italic> mutants to maintain efficient replication and successful propagation. Flies that exhibit these metabolic effects also show reduced food intake, which highlights the complicated neurological defects associated with ZIKV. We show that ZIKV infection significantly reduces insulin gene expression in <jats:italic>Dicer-2<\/jats:italic> mutants, suggesting an insulin antiviral role against ZIKV and a direct connection to RNAi immunity. Moreover, we find that the insulin receptor substrate c<jats:italic>hico<\/jats:italic> is crucial to the survival of ZIKV-infected flies. These observations are remarkably more severe in adult female flies compared to males, indicating possible sex differences in the rates of infection and susceptibility to the development of disease. Such findings not only demonstrate that metabolic alterations can be potentially exploited for developing immune therapeutic strategies but also that preventive measures for disease development may require sex-specific approaches. Therefore, further studies are urgently needed to explore the molecular factors that could be considered as targets to inhibit ZIKV manipulation of host cell metabolism in females and males.<\/jats:p>","DOI":"10.3389\/fimmu.2022.903860","type":"journal-article","created":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T07:36:39Z","timestamp":1656574599000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Zika Virus Induces Sex-Dependent Metabolic Changes in Drosophila melanogaster to Promote Viral Replication"],"prefix":"10.3389","volume":"13","author":[{"given":"Ghada","family":"Tafesh-Edwards","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ananda","family":"Kalukin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Eleftherianos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"54","DOI":"10.20546\/ijcmas.2021.1012.008","article-title":"Study on Vector Dynamics of Zika Virus Outbreak in Thiruvananthapuram, Kerala, India","volume":"10","author":"Sasi","year":"2021","journal-title":"Int J Curr Microbiol App Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/med.21786","article-title":"Recent Progresses and Remaining Challenges for the Detection of Zika Virus","volume":"41","author":"Zhang","year":"2021","journal-title":"Med Res Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0246643","article-title":"Fetal, Neonatal, and Infant Outcomes Associated With Maternal Zika Virus Infection During Pregnancy: A Systematic Review and Meta-Analysis","volume":"16","author":"Martins","year":"2021","journal-title":"PLoS One"},{"key":"B4","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1080\/20469047.2020.1776044","article-title":"Zika Virus in Brazil and Worldwide: A Narrative Review","volume":"41","author":"Martins","year":"2021","journal-title":"Paediatr Int Child Health"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2105\/AJPH.2018.304849","article-title":"Emerging and Reemerging Aedes-Transmitted Arbovirus Infections in the Region of the Americas: Implications for Health Policy","volume":"109","author":"Espinal","year":"2019","journal-title":"Am J Public Health"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-017-2453-9","article-title":"Innate and Intrinsic Antiviral Immunity in Drosophila","volume":"74","author":"Mussabekova","year":"2017","journal-title":"Cell Mol Life Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02973","article-title":"Emerging Mechanisms of Insulin-Mediated Antiviral Immunity in Drosophila Melanogaster","volume":"20","author":"Trammell","year":"2019","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.virol.2011.11.016","article-title":"Drosophila as a Genetic Model for Studying Pathogenic Human Viruses","volume":"423","author":"Hughes","year":"2012","journal-title":"Virol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2019.12.001","article-title":"Drosophila Immunity Against Natural and Nonnatural Viral Pathogens","volume":"15","author":"Tafesh-Edwards","year":"2020","journal-title":"Virol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.virol.2020.01.010","article-title":"Drosophila Melanogaster as a Model for Arbovirus Infection of Adult Salivary Glands","volume":"543","author":"Palmer","year":"2020","journal-title":"Virol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800597","article-title":"Dicer-2 Regulates Resistance and Maintains Homeostasis Against Zika Virus Infection in","volume":"201","author":"Harsh","year":"2018","journal-title":"Drosophila. J Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"dmm040816","DOI":"10.1242\/dmm.040816","article-title":"Zika Virus Non-Structural Protein NS4A Restricts Eye Growth in Drosophila Through Regulation of JAK\/STAT Signaling","volume":"13","author":"Harsh","year":"2020","journal-title":"Dis Model Mech"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2018.1528813","article-title":"Zika Virus Infection Activates Sting-Dependent Antiviral Autophagy in the Drosophila Brain","volume":"15","author":"Liu","year":"2019","journal-title":"Autophagy"},{"key":"B14","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.devcel.2019.10.009","article-title":"Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly","volume":"51","author":"Link","year":"2019","journal-title":"Dev Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nri2824","article-title":"RNA-Based Antiviral Immunity","volume":"10","author":"Ding","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.112408.134243","article-title":"Viruses, MicroRNAs, and Host Interactions","volume":"64","author":"Skalsky","year":"2010","journal-title":"Annu Rev Microbiol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/nri3763","article-title":"Immunity in Drosophila Melanogaster \u2014 From Microbial Recognition to Whole-Organism Physiology","volume":"14","author":"Buchon","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/ni0202-121","article-title":"Drosophila Innate Immunity: An Evolutionary Perspective","volume":"3","author":"Hoffmann","year":"2002","journal-title":"Nat Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.coi.2019.11.008","article-title":"New Insights on Drosophila Antimicrobial Peptide Function in Host Defense and Beyond","volume":"62","author":"Hanson","year":"2020","journal-title":"Curr Opin Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nri2194","article-title":"The Drosophila Systemic Immune Response: Sensing and Signalling During Bacterial and Fungal Infections","volume":"7","author":"Ferrandon","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.dci.2020.103985","article-title":"Sensing and Signalling Viral Infection in Drosophila","volume":"117","author":"Schneider","year":"2021","journal-title":"Dev Comp Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/v10050230","article-title":"Defense Mechanisms Against Viral Infection in Drosophila: RNAi and Non-RNAi","volume":"10","author":"Swevers","year":"2018","journal-title":"Viruses"},{"key":"B23","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/bs.ircmb.2018.11.002","article-title":"Nucleic Acid Sensing in Invertebrate Antiviral Immunity","volume":"345","author":"Wang","year":"2019","journal-title":"Int Rev Cell Mol Biol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/science.1125694","article-title":"RNA Interference Directs Innate Immunity Against Viruses in Adult Drosophila","volume":"312","author":"Wang","year":"2006","journal-title":"Science"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01778-21","article-title":"Enoxacin Shows Broad-Spectrum Antiviral Activity Against Diverse Viruses by Enhancing Antiviral RNA Interference in Insects","volume":"96","author":"Lyu","year":"2022","journal-title":"Virol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.chom.2018.05.022","article-title":"Inflammation-Induced, STING-Dependent Autophagy Restricts Zika Virus Infection in the Drosophila Brain","volume":"24","author":"Liu","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.117.199885","article-title":"Regulation of Carbohydrate Energy Metabolism in Drosophila Melanogaster","volume":"207","author":"Mattila","year":"2017","journal-title":"Genetics"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Realtime Quantitative PCR, and the 2\u201311CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing Real-Time PCR Data by the Comparative CT Method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat Protoc"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2899","article-title":"Quantifying Drosophila Food Intake: Comparative Analysis of Current Methodology","volume":"11","author":"Deshpande","year":"2014","journal-title":"Nat Methods"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2014.02.034","article-title":"Methods for Studying Metabolism in Drosophila","volume":"68","author":"Tennessen","year":"2014","journal-title":"Methods"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1080\/19336934.2016.1207029","article-title":"Infection Avoidance Behavior: Viral Exposure Reduces the Motivation to Forage in Female Drosophila Melanogaster","volume":"11","author":"Vale","year":"2017","journal-title":"Fly (Austin)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.jinsphys.2015.08.005","article-title":"Sex-Specific Behavioural Symptoms of Viral Gut Infection and Wolbachia in Drosophila Melanogaster","volume":"82","author":"Vale","year":"2015","journal-title":"J Insect Physiol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.cobeha.2015.08.002","article-title":"Behavioral Competence: How Host Behaviors Can Interact to Influence Parasite Transmission Risk","volume":"6","author":"Barron","year":"2015","journal-title":"Curr Opin Behav Sci"},{"key":"B35","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1042\/BJ20091181","article-title":"Molecular Mechanisms of Metabolic Regulation by Insulin in Drosophila","volume":"425","author":"Teleman","year":"2009","journal-title":"Biochem J"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1016\/j.celrep.2019.10.029","article-title":"Insulin Potentiates JAK\/STAT Signaling to Broadly Inhibit Flavivirus Replication in Insect Vectors","volume":"29","author":"Ahlers","year":"2019","journal-title":"Cell Rep"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1664","article-title":"The DExD\/H-Box Helicase Dicer-2 Mediates the Induction of Antiviral Activity in Drosophila","volume":"9","author":"Deddouche","year":"2008","journal-title":"Nat Immunol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.antiviral.2015.04.010","article-title":"The Dengue Virus NS5 Protein as a Target for Drug Discovery","volume":"119","author":"Lim","year":"2015","journal-title":"Antiviral Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14763","article-title":"The Structure of Zika Virus NS5 Reveals a Conserved Domain Conformation","volume":"8","author":"Wang","year":"2017","journal-title":"Nat Commun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.13437","article-title":"Zika Virus Nonstructural Protein 5 Residue R681 Is Critical for Dimer Formation and Enzymatic Activity","volume":"593","author":"Saw","year":"2019","journal-title":"FEBS Lett"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.dci.2015.12.006","article-title":"Insect Immunology and Hematopoiesis","volume":"58","author":"Hillyer","year":"2016","journal-title":"Dev Comp Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2666-18.2019","article-title":"Mouse Strain and Sex-Dependent Differences in Long-Term Behavioral Abnormalities and Neuropathologies After Developmental Zika Infection","volume":"39","author":"Snyder-Keller","year":"2019","journal-title":"J Neurosci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg4336","article-title":"What Fuels the Fly: Energy Metabolism in Drosophila and its Application to the Study of Obesity and Diabetes","volume":"7","author":"Chatterjee","year":"2021","journal-title":"Sci Adv"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.012989","article-title":"Modeling Metabolic Homeostasis and Nutrient Sensing in Drosophila: Implications for Aging and Metabolic Diseases","volume":"7","author":"Owusu-Ansah","year":"2014","journal-title":"Dis Model Mech"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02309\u201314","article-title":"Dengue Virus Induces and Requires Glycolysis for Optimal Replication","volume":"89","author":"Fontaine","year":"2015","journal-title":"J Virol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22052495","article-title":"Zika Virus Growth in Human Kidney Cells Is Restricted by an Elevated Glucose Level","volume":"22","author":"Reslan","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3390\/v14020377","article-title":"Zika Virus Infection of Sertoli Cells Alters Protein Expression Involved in Activated Immune and Antiviral Response Pathways, Carbohydrate Metabolism and Cardiovascular Disease","volume":"14","author":"Rashid","year":"2022","journal-title":"Viruses"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2015.02.038","article-title":"Viral Activation of Cellular Metabolism","author":"Sanchez","year":"2015","journal-title":"Virol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1093\/abbs\/gms105","article-title":"Lipid Metabolism in Drosophila: Development and Disease","volume":"45","author":"Liu","year":"2013","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2013.00385","article-title":"Independent Signaling by Drosophila Insulin Receptor for Axon Guidance and Growth","volume":"4","author":"Li","year":"2014","journal-title":"Front Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)80799-0","article-title":"Autonomous Control of Cell and Organ Size by CHICO, a Drosophila Homolog of Vertebrate IRS1-4","volume":"97","author":"B\u00f6hni","year":"1999","journal-title":"Cell"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1126\/science.1057991","article-title":"Extension of Life-Span by Loss of CHICO, a Drosophila Insulin Receptor Substrate Protein","volume":"292","author":"Clancy","year":"2001","journal-title":"Science"},{"key":"B53","article-title":"Insulin, IGF-1 and Longevity","volume":"1","author":"van Heemst","year":"2010","journal-title":"Aging Dis"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1517124112","article-title":"FOXO Regulates RNA Interference in Drosophila and Protects From RNA Virus Infection","volume":"112","author":"Spellberg","year":"2015","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.903860\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T07:36:42Z","timestamp":1656574602000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.903860\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,30]]},"references-count":54,"alternative-id":["10.3389\/fimmu.2022.903860"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.903860","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,30]]},"article-number":"903860"}}