{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T11:12:00Z","timestamp":1756897920862,"version":"3.41.2"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"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. Microbiol."],"abstract":"<jats:p>Influenza A virus (IAV) is a major respiratory pathogen that causes seasonal and pandemic flu, being a threat to global health. Various viral and cellular factors have been characterized to support or limit IAV infection. Interleukin 16 (IL16) has been known as one of the blood signature biomarkers discriminating systemic inflammation due to viral infection vs. other etiologies. Here, we report that the level of IL16 was elevated in the serum samples, lung homogenates, and bronchoalveolar lavage fluid of IAV-infected mice. IL16 overexpression facilitated IAV replication. Conversely, loss of IL16 reduced the host susceptibility to IAV infection<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>. Furthermore, IL16 deficiency blocked IAV-induced body weight loss and attenuated lung injury in the infected mice. Molecular mechanism analyses further revealed that IL16 could directly inhibit IFN-\u03b2 transcription and suppress the expression of IFN-\u03b2 and IFN-stimulated gene. In conclusion, these findings demonstrate that IL16 is a supporting factor for IAV infection.<\/jats:p>","DOI":"10.3389\/fmicb.2021.736449","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T14:31:00Z","timestamp":1632407460000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Interleukin 16 Enhances the Host Susceptibility to Influenza A Virus Infection"],"prefix":"10.3389","volume":"12","author":[{"given":"Ran","family":"Jia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congwei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenxu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijuan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Menghua","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaozhen","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1086\/314550","article-title":"Interleukin-16 (IL-16) inhibits human immunodeficiency virus replication in cells from infected subjects, and serum IL-16 levels drop with disease progression","volume":"179","author":"Amiel","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/378563a0","article-title":"HIV suppression by interleukin-16","volume":"378","author":"Baier","year":"1995","journal-title":"Nature"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.cyto.2018.05.038","article-title":"Ablation of the CD9 receptor in human lung cancer cells using CRISPR\/Cas alters migration to chemoattractants including IL-16","volume":"111","author":"Blake","year":"2018","journal-title":"Cytokine"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1016\/0167-5699(96)10052-I","article-title":"Interleukin 16 and its function as a CD4 ligand","volume":"17","author":"Center","year":"1996","journal-title":"Immunol. 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Biol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1182\/blood-2012-07-442558","article-title":"Comparison of primary human cytotoxic T-cell and natural killer cell responses reveal similar molecular requirements for lytic granule exocytosis but differences in cytokine production","volume":"121","author":"Chiang","year":"2013","journal-title":"Blood"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"5109","DOI":"10.1073\/pnas.91.11.5109","article-title":"Molecular and functional analysis of a lymphocyte chemoattractant factor: association of biologic function with CD4 expression","volume":"91","author":"Cruikshank","year":"1994","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"4465","DOI":"10.4049\/jimmunol.174.8.4465","article-title":"Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation","volume":"174","author":"Curtsinger","year":"2005","journal-title":"J. Immunol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"4523","DOI":"10.1128\/JVI.02548-12","article-title":"TRIM22 inhibits influenza A virus infection by targeting the viral nucleoprotein for degradation","volume":"87","author":"Di Pietro","year":"2013","journal-title":"J. Virol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.3389\/fimmu.2018.01581","article-title":"Influenza A virus cell entry, replication, virion assembly and movement","volume":"9","author":"Dou","year":"2018","journal-title":"Front. Immunol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1038\/nrmicro3367","article-title":"At the Centre: influenza A virus ribonucleoproteins","volume":"13","author":"Eisfeld","year":"2015","journal-title":"Nat. Rev. Microbiol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"e1004960","DOI":"10.1371\/journal.ppat.1004960","article-title":"TRIM32 senses and restricts influenza A virus by ubiquitination of PB1 polymerase","volume":"11","author":"Fu","year":"2015","journal-title":"PLoS Pathog."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e21207","DOI":"10.1371\/journal.pone.0021207","article-title":"Serial histopathological examination of the lungs of mice infected with influenza A virus PR8 strain","volume":"6","author":"Fukushi","year":"2011","journal-title":"PLoS One"},{"key":"ref15","first-page":"538","article-title":"Interleukin-16 does not suppress HIV-1 replication in naturally infected peripheral blood mononuclear cells","volume":"11","author":"Gao","year":"1997","journal-title":"AIDS"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/j.immuni.2011.07.012","article-title":"Structure of myxovirus resistance protein a reveals intra- and intermolecular domain interactions required for the antiviral function","volume":"35","author":"Gao","year":"2011","journal-title":"Immunity"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"8550","DOI":"10.1128\/JVI.72.11.8550-8558.1998","article-title":"The role of interferon in influenza virus tissue tropism","volume":"72","author":"Garcia-Sastre","year":"1998","journal-title":"J. Virol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1183\/09031936.00186214","article-title":"Influenza virus-induced lung injury: pathogenesis and implications for treatment","volume":"45","author":"Herold","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"2541","DOI":"10.1056\/NEJMc1111078","article-title":"Community transmission of oseltamivir-resistant A(H1N1)pdm09 influenza","volume":"365","author":"Hurt","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/nri3581","article-title":"Regulation of type I interferon responses","volume":"14","author":"Ivashkiv","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/nri3665","article-title":"Innate immunity to influenza virus infection","volume":"14","author":"Iwasaki","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"9790","DOI":"10.1128\/JVI.00530-07","article-title":"Differential type I interferon induction by respiratory syncytial virus and influenza a virus in vivo","volume":"81","author":"Jewell","year":"2007","journal-title":"J. Virol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"516","DOI":"10.5582\/bst.2019.01286","article-title":"IL16 deficiency enhances Th1 and cytotoxic T lymphocyte response against influenza A virus infection","volume":"13","author":"Jia","year":"2020","journal-title":"Biosci. Trends"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2025","DOI":"10.1128\/JVI.01718-06","article-title":"Protective role of beta interferon in host defense against influenza A virus","volume":"81","author":"Koerner","year":"2007","journal-title":"J. Virol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1038\/nature08699","article-title":"Human host factors required for influenza virus replication","volume":"463","author":"Konig","year":"2010","journal-title":"Nature"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/s41577-019-0143-6","article-title":"The human antibody response to influenza A virus infection and vaccination","volume":"19","author":"Krammer","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/nrd4529","article-title":"Advances in the development of influenza virus vaccines","volume":"14","author":"Krammer","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.cytogfr.2007.10.007","article-title":"Type I interferon as a stimulus for cross-priming","volume":"19","author":"Le Bon","year":"2008","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"4929","DOI":"10.3390\/v7092850","article-title":"Clinical implications of antiviral resistance in influenza","volume":"7","author":"Li","year":"2015","journal-title":"Viruses"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"e1008701","DOI":"10.1371\/journal.ppat.1008701","article-title":"Interleukin 16 contributes to gammaherpesvirus pathogenesis by inhibiting viral reactivation","volume":"16","author":"Liu","year":"2020","journal-title":"PLoS Pathog."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"4369","DOI":"10.1128\/JVI.03172-15","article-title":"The C-terminal tail of TRIM56 dictates antiviral restriction of influenza A and B viruses by impeding viral RNA synthesis","volume":"90","author":"Liu","year":"2016","journal-title":"J. Virol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1084\/jem.20090247","article-title":"Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant","volume":"206","author":"Longhi","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref33","doi-asserted-by":"crossref","first-page":"5","DOI":"10.4049\/jimmunol.158.1.5","article-title":"IL-16 represses HIV-1 promoter activity","volume":"158","author":"Maciaszek","year":"1997","journal-title":"J. Immunol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1084\/jem.20150712","article-title":"Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide","volume":"213","author":"Madera","year":"2016","journal-title":"J. Exp. 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Virol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1182\/blood-2005-03-1312","article-title":"Human and mouse mast cells use the tetraspanin CD9 as an alternate interleukin-16 receptor","volume":"107","author":"Qi","year":"2006","journal-title":"Blood"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/nri2314","article-title":"Interferon-inducible antiviral effectors","volume":"8","author":"Sadler","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref40","first-page":"153","article-title":"Influenza A: understanding the viral life cycle","volume":"82","author":"Samji","year":"2009","journal-title":"Yale J. Biol. Med."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2914","DOI":"10.1038\/s41598-017-02325-8","article-title":"A four-biomarker blood signature discriminates systemic inflammation due to viral infection versus other etiologies","volume":"7","author":"Sampson","year":"2017","journal-title":"Sci. Rep."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"223","DOI":"10.3390\/v9080223","article-title":"Influenza virus infection, interferon response, viral counter-response, and apoptosis","volume":"9","author":"Shim","year":"2017","journal-title":"Viruses"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1586\/14760584.2013.814871","article-title":"Type I interferon regulation of natural killer cell function in primary and secondary infections","volume":"12","author":"Stackaruk","year":"2013","journal-title":"Expert Rev. Vaccines"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"9782","DOI":"10.1128\/JVI.00668-16","article-title":"CD95 signaling inhibits B cell receptor-mediated gammaherpesvirus replication in apoptosis-resistant B lymphoma cells","volume":"90","author":"Tan","year":"2016","journal-title":"J. Virol."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1146\/annurev.pathmechdis.3.121806.154316","article-title":"The pathology of influenza virus infections","volume":"3","author":"Taubenberger","year":"2008","journal-title":"Annu. Rev. Pathol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/nrmicro.2016.87","article-title":"Influenza virus RNA polymerase: insights into the mechanisms of viral RNA synthesis","volume":"14","author":"Te Velthuis","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"7008","DOI":"10.1128\/JVI.73.8.7008-7013.1999","article-title":"Interleukin-16 inhibits human immunodeficiency virus type 1 entry and replication in macrophages and in dendritic cells","volume":"73","author":"Truong","year":"1999","journal-title":"J. Virol."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"376","DOI":"10.3390\/v9120376","article-title":"Host cell restriction factors that limit influenza A infection","volume":"9","author":"Villalon-Letelier","year":"2017","journal-title":"Viruses"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"183","DOI":"10.3109\/15476911003649346","article-title":"IL-16 effects on A549 lung epithelial cells: dependence on CD9 as an IL-16 receptor?","volume":"7","author":"Yadav","year":"2010","journal-title":"J. Immunotoxicol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1006\/cimm.2000.1745","article-title":"Interleukin (IL)-4\/IL-9 and exogenous IL-16 induce IL-16 production by BEAS-2B cells, a bronchial epithelial cell line","volume":"207","author":"Yoshida","year":"2001","journal-title":"Cell. Immunol."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"262","DOI":"10.3389\/fmicb.2016.00262","article-title":"Full genome characterization of human influenza A\/H3N2 isolates from Asian countries reveals a rare amantadine resistance-conferring mutation and novel PB1-F2 polymorphisms","volume":"7","author":"Zaraket","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1128\/JCM.01532-09","article-title":"Genetic makeup of amantadine-resistant and oseltamivir-resistant human influenza A\/H1N1 viruses","volume":"48","author":"Zaraket","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1074\/jbc.273.2.1144","article-title":"Processing and activation of pro-interleukin-16 by caspase-3","volume":"273","author":"Zhang","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"2253","DOI":"10.1073\/pnas.0909144107","article-title":"ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells","volume":"107","author":"Zhao","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/nm0697-659","article-title":"Human CD4+ cells transfected with IL-16 cDNA are resistant to HIV-1 infection: inhibition of mRNA expression","volume":"3","author":"Zhou","year":"1997","journal-title":"Nat. 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