{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T23:56:17Z","timestamp":1789775777346,"version":"4.0.1"},"reference-count":29,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T00:00:00Z","timestamp":1628208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/M008681\/1"],"award-info":[{"award-number":["BB\/M008681\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BBS\/E\/I\/00001852"],"award-info":[{"award-number":["BBS\/E\/I\/00001852"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000308","name":"British Council","doi-asserted-by":"publisher","award":["172710323"],"award-info":[{"award-number":["172710323"]}],"id":[{"id":"10.13039\/501100000308","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mammalian cells utilize a wide spectrum of pathways to antagonize the viral replication. These pathways are typically regulated by antiviral proteins and can be constitutively expressed but also exacerbated by interferon induction. A myriad of interferon-stimulated genes (ISGs) have been identified in mounting broad-spectrum antiviral responses. Members of the interferon-induced transmembrane (IFITM) family of proteins are unique among these ISGs due to their ability to prevent virus entry through the lipid bilayer into the cell. In the current study, we generated transgenic chickens that constitutively and stably expressed chicken IFITM1 (chIFITM1) using the avian sarcoma-leukosis virus (RCAS)-based gene transfer system. The challenged transgenic chicks with clinical dose 104 egg infective dose 50 (EID50) of highly pathogenic avian influenza virus (HPAIV) subtype H5N1 (clade 2.2.1.2) showed 100% protection and significant infection tolerance. Although challenged transgenic chicks displayed 60% protection against challenge with the sub-lethal dose (EID50 105), the transgenic chicks showed delayed clinical symptoms, reduced virus shedding, and reduced histopathologic alterations compared to non-transgenic challenged control chickens. These finding indicate that the sterile defense against H5N1 HPAIV offered by the stable expression of chIFITM1 is inadequate; however, the clinical outcome can be substantially ameliorated. In conclusion, chIFITM proteins can inhibit influenza virus replication that can infect various host species and could be a crucial barrier against zoonotic infections.<\/jats:p>","DOI":"10.3390\/ijms22168456","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T08:01:42Z","timestamp":1628236902000},"page":"8456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Transgenic Chicks Expressing Interferon-Inducible Transmembrane Protein 1 (IFITM1) Restrict Highly Pathogenic H5N1 Influenza Viruses"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6941-9294","authenticated-orcid":false,"given":"Mohammed A.","family":"Rohaim","sequence":"first","affiliation":[{"name":"Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YG, UK"},{"name":"Department of Virology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Q.","family":"Al-Natour","sequence":"additional","affiliation":[{"name":"Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YG, UK"},{"name":"Department of Veterinary Pathology & Public Health, Faculty of Veterinary Medicine, Jordan University of Science and Technology (JUST), P.O. Box 3030, Irbid 22110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed A.","family":"Abdelsabour","sequence":"additional","affiliation":[{"name":"Department of Poultry Viral Vaccines, Veterinary Serum and Vaccine Research Institute (VSVRI), Agriculture Research Centre (ARC), Cairo 11435, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3648-847X","authenticated-orcid":false,"given":"Rania F.","family":"El Naggar","sequence":"additional","affiliation":[{"name":"Department of Virology, Faculty of Veterinary Medicine, University of Sadat City, Sadat 32897, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahia M.","family":"Madbouly","sequence":"additional","affiliation":[{"name":"Department of Poultry Viral Vaccines, Veterinary Serum and Vaccine Research Institute (VSVRI), Agriculture Research Centre (ARC), Cairo 11435, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7376-7411","authenticated-orcid":false,"given":"Kawkab A.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4038-0370","authenticated-orcid":false,"given":"Muhammad","family":"Munir","sequence":"additional","affiliation":[{"name":"Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4937","DOI":"10.1016\/j.jmb.2013.09.024","article-title":"IFITMs restrict the replication of multiple pathogenic viruses","volume":"425","author":"Perreira","year":"2013","journal-title":"J. Mol. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nri3344","article-title":"The broad-spectrum antiviral functions of IFIT and IFITM proteins","volume":"13","author":"Diamond","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Li, K., Markosyan, R.M., Zheng, Y.-M., Golfetto, O., Bungart, B., Li, M., Ding, S., He, Y., Liang, C., and Lee, J.C. (2013). IFITM proteins restrict viral membrane hemifusion. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003124"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/j.cell.2009.12.017","article-title":"The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus","volume":"139","author":"Brass","year":"2009","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Huang, I.-C., Bailey, C.C., Weyer, J.L., Radoshitzky, S.R., Becker, M.M., Chiang, J.J., Brass, A.L., Ahmed, A.A., Chi, X., and Dong, L. (2011). Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1001258"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1128\/JVI.01531-10","article-title":"The IFITM proteins inhibit HIV-1 infection","volume":"85","author":"Lu","year":"2011","journal-title":"J. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12957","DOI":"10.1128\/JVI.01443-13","article-title":"Chicken interferon-inducible transmembrane protein 3 restricts influenza viruses and lyssaviruses in vitro","volume":"87","author":"Smith","year":"2013","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/hep.26066","article-title":"IFITM1 is a tight junction protein that inhibits hepatitis C virus entry","volume":"57","author":"Wilkins","year":"2013","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.3390\/v7062759","article-title":"IFITMs from Mycobacteria Confer Resistance to Influenza Virus When Expressed in Human Cells","volume":"7","author":"Melvin","year":"2015","journal-title":"Viruses"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1089\/jir.2010.0112","article-title":"The small interferon-induced transmembrane genes and proteins","volume":"31","author":"Siegrist","year":"2011","journal-title":"J. Interferon. Cytokine Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Smith, J., Smith, N., Yu, L., Paton, I.R., Gutowska, M.W., Forrest, H.L., Danner, A.F., Seiler, J.P., Digard, P., and Webster, R.G. (2015). A comparative analysis of host responses to avian influenza infection in ducks and chickens highlights a role for the interferon-induced transmembrane proteins in viral resistance. BMC Genom., 16.","DOI":"10.1186\/s12864-015-1778-8"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1016\/j.vaccine.2012.04.049","article-title":"Adaptive pathways of zoonotic influenza viruses: From exposure to establishment in humans","volume":"30","author":"Reperant","year":"2012","journal-title":"Vaccine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.3389\/fimmu.2018.02025","article-title":"Chickens Expressing IFIT5 Ameliorate Clinical Outcome and Pathology of Highly Pathogenic Avian Influenza and Velogenic Newcastle Disease Viruses","volume":"9","author":"Rohaim","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1146\/annurev.micro.62.081307.162746","article-title":"Host restriction of avian influenza viruses at the level of the ribonucleoproteins","volume":"62","author":"Naffakh","year":"2008","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_15","first-page":"107","article-title":"The RCAS vector system","volume":"50","author":"Hughes","year":"2004","journal-title":"Folia Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.1128\/JVI.02764-13","article-title":"Antiviral activity of lambda interferon in chickens","volume":"88","author":"Reuter","year":"2014","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.3201\/eid1211.060426","article-title":"Review of aerosol transmission of influenza A virus","volume":"12","author":"Tellier","year":"2006","journal-title":"Emerg. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1111\/tbed.12472","article-title":"Re-Emergence of a Novel H5N1 Avian Influenza Virus Variant Subclade 2.2.1.1 in Egypt During 2014","volume":"64","author":"Rohaim","year":"2017","journal-title":"Transbound Emerg. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kilany, W.H., Safwat, M., Mohammed, S.M., Salim, A., Fasina, F.O., Fasanmi, O.G., Shalaby, A.G., Dauphin, G., Hassan, M.K., and Lubroth, J. (2016). Protective Efficacy of Recombinant Turkey Herpes Virus (rHVT-H5) and Inactivated H5N1 Vaccines in Commercial Mulard Ducks against the Highly Pathogenic Avian Influenza (HPAI) H5N1 Clade 2.2.1 Virus. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156747"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6289","DOI":"10.3382\/ps\/pez385","article-title":"Development of an effective contemporary trivalent avian influenza vaccine against circulating H5N1, H5N8, and H9N2 in Egypt","volume":"98","author":"Gomaa","year":"2019","journal-title":"Poult. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5913","DOI":"10.1073\/pnas.1001755107","article-title":"Association of RIG-I with innate immunity of ducks to influenza","volume":"107","author":"Barber","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1016\/j.molimm.2010.01.011","article-title":"Prolonged effect of BAFF on chicken B cell development revealed by RCAS retroviral gene transfer in vivo","volume":"47","author":"Kothlow","year":"2010","journal-title":"Mol. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.chom.2013.03.006","article-title":"The antiviral effector IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry","volume":"13","author":"Choi","year":"2013","journal-title":"Cell Host Microbe."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6794","DOI":"10.1038\/s41598-018-24905-y","article-title":"Chicken Interferon-induced Protein with Tetratricopeptide Repeats 5 Antagonizes Replication of RNA Viruses","volume":"8","author":"Santhakumar","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1038\/s41598-017-02951-2","article-title":"Chicken IFN Kappa: A Novel Cytokine with Antiviral Activities","volume":"7","author":"Santhakumar","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","first-page":"493","article-title":"A Simple Method of Estimating Fifty Percent Endpoints","volume":"27","author":"Reed","year":"1938","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_28","unstructured":"OIE (2012). Manual of Diagnostic Tests and Vaccines for Terrestrial Animals, OIE. [7th ed.]."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Landmann, M., Scheibner, D., Graaf, A., Gischke, M., Koethe, S., Fatola, O.I., Raddatz, B., Mettenleiter, T.C., Beer, M., and Grund, C. (2021). A Semiquantitative Scoring System for Histopathological and Immunohistochemical Assessment of Lesions and Tissue Tropism in Avian Influenza. Viruses, 13.","DOI":"10.3390\/v13050868"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8456\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:41:38Z","timestamp":1760164898000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,6]]},"references-count":29,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168456"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168456","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,6]]}}}