{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:20:57Z","timestamp":1790720457773,"version":"4.1.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"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>The Epstein-Barr virus (EBV) commonly infects humans and is highly associated with different types of cancers and autoimmune diseases. EBV has also been detected in inflamed gastrointestinal mucosa of patients suffering from prolonged inflammation of the digestive tract such as inflammatory bowel disease (IBD) with no clear role identified yet for EBV in the pathology of such diseases. Since we have previously reported immune-stimulating capabilities of EBV DNA in various models, in this study we investigated whether EBV DNA may play a role in exacerbating intestinal inflammation through innate immune and regeneration responses using the <jats:italic>Drosophila melanogaster<\/jats:italic> model. We have generated inflamed gastrointestinal tracts in adult fruit flies through the administration of dextran sodium sulfate (DSS), a sulfated polysaccharide that causes human ulcerative colitis- like pathologies due to its toxicity to intestinal cells. Intestinal damage induced by inflammation recruited plasmatocytes to the ileum in fly hindguts. EBV DNA aggravated inflammation by enhancing the immune deficiency (IMD) pathway as well as further increasing the cellular inflammatory responses manifested upon the administration of DSS. The study at hand proposes a possible immunostimulatory role of the viral DNA exerted specifically in the fly hindgut hence further developing our understanding of immune responses mounted against EBV DNA in the latter intestinal segment of the <jats:italic>D. melanogaster<\/jats:italic> gut. These findings suggest that EBV DNA may perpetuate proinflammatory processes initiated in an inflamed digestive system. Our findings indicate that <jats:italic>D. melanogaster<\/jats:italic> can serve as a model to further understand EBV-associated gastroinflammatory pathologies. Further studies employing mammalian models may validate the immunogenicity of EBV DNA in an IBD context and its role in exacerbating the disease through inflammatory mediators.<\/jats:p>","DOI":"10.3389\/fimmu.2021.586930","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T06:17:35Z","timestamp":1616393855000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Drosophila melanogaster as a Model System to Assess the Effect of Epstein-Barr Virus DNA on Inflammatory Gut Diseases"],"prefix":"10.3389","volume":"12","author":[{"given":"Joelle R.","family":"Madi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amani Al","family":"Outa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirna","family":"Ghannam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadi M.","family":"Hussein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa","family":"Shehab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeinab Al Kobra Haj","family":"Hasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine Abou","family":"Fayad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margret","family":"Shirinian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias A.","family":"Rahal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/path.2487","article-title":"The ATM tumour suppressor gene is down-regulated in EBV-associated nasopharyngeal carcinoma","volume":"217","author":"Bose","year":"2009","journal-title":"J Pathol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2007.12.003","article-title":"ATM mediates repression of DNA end-degradation in an ATP-dependent manner","volume":"7","author":"Rahal","year":"2008","journal-title":"DNA Repair (Amst)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.043265-0","article-title":"Three-dimensional structure of the Epstein-Barr virus capsid","volume":"93","author":"Germi","year":"2012","journal-title":"J Gen Virol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1080\/1040841X.2019.1614904","article-title":"The role of viral infections in the development of autoimmune diseases","volume":"45","author":"Hussein","year":"2019","journal-title":"Crit Rev Microbiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903736","article-title":"TLR9 Contributes to the Recognition of EBV by Primary Monocytes and Plasmacytoid Dendritic Cells","volume":"185","author":"Fiola","year":"2010","journal-title":"J Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1089\/vim.2014.0129","article-title":"Epstein-Barr Virus and Human herpes virus 6 Type A DNA Enhance IL-17 Production in Mice","volume":"28","author":"Rahal","year":"2015","journal-title":"Viral Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00987-19","article-title":"Endosomal Toll-Like Receptors Mediate Enhancement of Interleukin-17A Production Triggered by Epstein-Barr Virus DNA in Mice","volume":"93","author":"Shehab","year":"2019","journal-title":"J Virol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e0200546","DOI":"10.1371\/journal.pone.0200546","article-title":"Epstein-Barr virus DNA modulates regulatory T-cell programming in addition to enhancing interleukin-17A production via Toll-like receptor 9","volume":"13","author":"Salloum","year":"2018","journal-title":"PLoS One"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.01268","article-title":"Epstein-Barr Virus DNA Enhances Diptericin Expression and Increases Hemocyte Numbers in Drosophila melanogaster via the Immune Deficiency Pathway","volume":"9","author":"Sherri","year":"2018","journal-title":"Front Microbiol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-012-2116-5","article-title":"Epstein-Barr virus infection is common in inflamed gastrointestinal mucosa","volume":"57","author":"Ryan","year":"2012","journal-title":"Dig Dis Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1086\/367988","article-title":"Prognostic factors for chronic active Epstein-Barr virus infection","volume":"187","author":"Kimura","year":"2003","journal-title":"J Infect Dis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.1890380306","article-title":"Detection of herpesvirus DNA in the large intestine of patients with ulcerative colitis and Crohn\u2019s disease using the nested polymerase chain reaction","volume":"38","author":"Wakefield","year":"1992","journal-title":"J Med Virol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64516-6","article-title":"Distribution and phenotype of Epstein-Barr virus-infected cells in inflammatory bowel disease","volume":"157","author":"Spieker","year":"2000","journal-title":"Am J Pathol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5107(00)70420-2","article-title":"Demonstration of Epstein-Barr virus localized in the colonic and ileal mucosa of a patient with ulcerative colitis","volume":"51","author":"Takeda","year":"2000","journal-title":"Gastrointest Endosc"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00918-15","article-title":"A Transgenic Drosophila melanogaster Model To Study Human T-Lymphotropic Virus Oncoprotein Tax-1-Driven Transformation In Vivo","volume":"89","author":"Shirinian","year":"2015","journal-title":"J Virol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1242\/dmm.003970","article-title":"Drosophila melanogaster as a model for human intestinal infection and pathology","volume":"4","author":"Apidianakis","year":"2011","journal-title":"Dis Model Mech"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208156","article-title":"Increased expression of Drosophila tetraspanin, Tsp68C, suppresses the abnormal proliferation of ytr-deficient and Ras\/Raf-activated hemocytes","volume":"23","author":"Sinenko","year":"2004","journal-title":"Oncogene"},{"key":"B18","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/gene.10137","article-title":"GETDB, a database compiling expression patterns and molecular locations of a collection of Gal4 enhancer traps","volume":"34","author":"Hayashi","year":"2002","journal-title":"Genesis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/annotation\/c3ebafa0-1531-4e9f-ab3a-660db7b8dcd2","article-title":"The Rap1 Guanine Nucleotide Exchange Factor C3G Is Required for Preservation of Larval Muscle Integrity in Drosophila melanogaster","volume":"5","author":"Shirinian","year":"2010","journal-title":"PLoS One"},{"key":"B20","article-title":"Prevalence of hepatitis C virus isolate genotypes from chronically infected Lebanese patients: a hospital-based study","volume":"51","author":"Irani-Hakime","year":"2003","journal-title":"J Med Liban"},{"key":"B21","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1186\/1756-0500-6-360","article-title":"Dextran sodium sulfate inhibits the activities of both polymerase and reverse transcriptase: lithium chloride purification, a rapid and efficient technique to purify RNA","volume":"6","author":"Viennois","year":"2013","journal-title":"BMC Res Notes"},{"key":"B22","doi-asserted-by":"crossref","DOI":"10.1007\/1-4020-3735-X_9","article-title":"RNA isolation using phase extraction and LiCl precipitation","volume-title":"Lotus japonicus Handbook","author":"Kistner","year":"2005"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5571","article-title":"Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age","volume":"6","author":"Fontebasso","year":"2015","journal-title":"Oncotarget"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1186\/1476-0711-10-34","article-title":"Decrease in Shiga toxin expression using a minimal inhibitory concentration of rifampicin followed by bactericidal gentamicin treatment enhances survival of Escherichia coli O157: H7-infected BALB\/c mice","volume":"10","author":"Rahal","year":"2011","journal-title":"Ann Clin Microbiol Antimicrob"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-5890(03)00073-7","article-title":"HLA class II allele frequencies in the Lebanese population","volume":"39","author":"Samaha","year":"2003","journal-title":"Mol Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1089\/fpd.2014.1824","article-title":"Effect of Rifampicin and Gentamicin on Shiga Toxin 2 Expression Level and the SOS Response in Escherichia coli O104:H4","volume":"12","author":"Fadlallah","year":"2015","journal-title":"Foodborne Pathog Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1179\/000349803235002146","article-title":"Inhibition of the transcription of the Escherichia coli O157 : H7 genes coding for shiga-like toxins and intimin, and its potential use in the treatment of human infection with the bacterium","volume":"97","author":"Matar","year":"2003","journal-title":"Ann Trop Med Parasitol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1155\/JBB.2005.310","article-title":"HLA allele associations and V-beta T-lymphocyte expansions in patients with psoriasis, harboring toxin-producing Staphylococcus aureus","volume":"2005","author":"Ajib","year":"2005","journal-title":"J BioMed Biotechnol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e76131","DOI":"10.1371\/journal.pone.0076131","article-title":"Expression patterns of the Drosophila neuropeptide CCHamide-2 and its receptor may suggest hormonal signaling from the gut to the brain","volume":"8","author":"Li","year":"2013","journal-title":"PLoS One"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2003.06.001","article-title":"Drosophila hemolectin gene is expressed in embryonic and larval hemocytes and its knock down causes bleeding defects","volume":"264","author":"Goto","year":"2003","journal-title":"Dev Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.dci.2011.10.013","article-title":"The Drosophila larva as a tool to study gut-associated macrophages: PI3K regulates a discrete hemocyte population at the proventriculus","volume":"36","author":"Zaidman-Remy","year":"2012","journal-title":"Dev Comp Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2007.02.041","article-title":"Nimrod, a putative phagocytosis receptor with EGF repeats in Drosophila plasmatocytes","volume":"17","author":"Kurucz","year":"2007","journal-title":"Curr Biol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14857","article-title":"Two Nimrod receptors, NimC1 and Eater, synergistically contribute to bacterial phagocytosis in Drosophila melanogaster","volume":"286","author":"Melcarne","year":"2019","journal-title":"FEBS J"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2202","article-title":"Drosophila melanogaster embryonic haemocytes: masters of multitasking","volume":"8","author":"Wood","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nature04371","article-title":"Evidence that stem cells reside in the adult Drosophila midgut epithelium","volume":"439","author":"Micchelli","year":"2006","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.stem.2008.10.016","article-title":"Tissue damage-induced intestinal stem cell division in Drosophila","volume":"4","author":"Amcheslavsky","year":"2009","journal-title":"Cell Stem Cell"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/535738","article-title":"Epstein-Barr Virus in Systemic Autoimmune Diseases","volume":"2013","author":"Draborg","year":"2013","journal-title":"Clin Dev Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4161\/gmic.22429","article-title":"Ras-oncogenic Drosophila hindgut but not midgut cells use an inflammation-like program to disseminate to distant sites","volume":"4","author":"Christofi","year":"2013","journal-title":"Gut Microbes"},{"key":"B39","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.chom.2014.12.012","article-title":"Bacterial uracil modulates Drosophila DUOX-dependent gut immunity via Hedgehog-induced signaling endosomes","volume":"17","author":"Lee","year":"2015","journal-title":"Cell Host Microbe"},{"key":"B40","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1146\/annurev.immunol.25.022106.141615","article-title":"The host defense of Drosophila melanogaster","volume":"25","author":"Lemaitre","year":"2007","journal-title":"Annu Rev Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.bbrc.2017.11.004","article-title":"Unexpected role of the IMD pathway in Drosophila gut defense against Staphylococcus aureus","volume":"495","author":"Hori","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"B42","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1084\/jem.192.4.595","article-title":"Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor\u2013associated factor (TRAF) 6","volume":"192","author":"H\u00e4cker","year":"2000","journal-title":"J Exp Med"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e1000655","DOI":"10.1371\/journal.ppat.1000655","article-title":"A quantitative RNAi screen for JNK modifiers identifies Pvr as a novel regulator of Drosophila immune signaling","volume":"5","author":"Bond","year":"2009","journal-title":"PLoS Pathog"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1086\/374758","article-title":"Drosophila melanogaster antimicrobial defense","author":"Hetru","year":"2003","journal-title":"J Infect Dis"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1992.tb05191.x","article-title":"Insect immunity: developmental and inducible activity of the Drosophila diptericin promoter","volume":"11","author":"Reichhart","year":"1992","journal-title":"EMBO J"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.586930\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T06:17:38Z","timestamp":1616393858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.586930\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,22]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2021.586930"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.586930","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,22]]},"article-number":"586930"}}