{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:41:29Z","timestamp":1792024889625,"version":"4.4.0"},"reference-count":50,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG052530"],"award-info":[{"award-number":["R01AG052530"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG056699"],"award-info":[{"award-number":["R01AG056699"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["K08HL138285"],"award-info":[{"award-number":["K08HL138285"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Influenza is a respiratory virus that alone or in combination with secondary bacterial pathogens can contribute to the development of acute pneumonia in persons &gt;65 years of age. Host innate immune antiviral signaling early in response to influenza is essential to inhibit early viral replication and guide the initiation of adaptive immune responses. Using young adult (3 months) and aged adult mice infected with mouse adapted H1N1 or H3N2, the results of our study illustrate dysregulated and\/or diminished activation of key signaling pathways in aged lung contribute to increased lung inflammation and morbidity. Specifically, within the first seven days of infection, there were significant changes in genes associated with TLR and RIG-I signaling detected in aged murine lung in response to H1N1 or H3N2. Taken together, the results of our study expand our current understanding of age-associated changes in antiviral signaling in the lung.<\/jats:p>","DOI":"10.3390\/ijms222212097","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T12:46:23Z","timestamp":1636461983000},"page":"12097","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Antiviral Gene Expression in Young and Aged Murine Lung during H1N1 and H3N2"],"prefix":"10.3390","volume":"22","author":[{"given":"Rebecca","family":"Harris","sequence":"first","affiliation":[{"name":"Weill Cornell Medicine, Division of Pulmonary and Critical Care, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Yang","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, Division of Pulmonary and Critical Care, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4971-1773","authenticated-orcid":false,"given":"Kassandra","family":"Pagan","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, Division of Pulmonary and Critical Care, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0759-7295","authenticated-orcid":false,"given":"Soo Jung","family":"Cho","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, Division of Pulmonary and Critical Care, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2387-6924","authenticated-orcid":false,"given":"Heather","family":"Stout-Delgado","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, Division of Pulmonary and Critical Care, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/S0140-6736(17)33293-2","article-title":"Global Seasonal Influenza-associated Mortality Collaborator, N. Estimates of global seasonal influenza-associated respiratory mortality: A modelling study","volume":"391","author":"Iuliano","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.rmed.2017.11.017","article-title":"National Influenza Apdm09 Clinical Investigation Group of, C., Risk factors for nosocomial infection among hospitalised severe influenza A(H1N1)pdm09 patients","volume":"134","author":"Zhou","year":"2018","journal-title":"Respir. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.addr.2007.11.005","article-title":"TLR3: Interferon induction by double-stranded RNA including poly(I:C)","volume":"60","author":"Matsumoto","year":"2008","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1126\/science.1087262","article-title":"Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway","volume":"301","author":"Yamamoto","year":"2003","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/ni886","article-title":"TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction","volume":"4","author":"Oshiumi","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16274","DOI":"10.1073\/pnas.0406268101","article-title":"Induction of antiviral immunity requires Toll-like receptor signaling in both stromal and dendritic cell compartments","volume":"101","author":"Sato","year":"2004","journal-title":"Proc. Natl. Acad Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/ni1112","article-title":"Toll-like receptor control of the adaptive immune responses","volume":"5","author":"Iwasaki","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5598","DOI":"10.1073\/pnas.0400937101","article-title":"Recognition of single-stranded RNA viruses by Toll-like receptor 7","volume":"101","author":"Lund","year":"2004","journal-title":"Proc. Natl. Acad Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8433","DOI":"10.1128\/JVI.00879-10","article-title":"The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon","volume":"84","author":"Graef","year":"2010","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.chom.2009.04.006","article-title":"Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I","volume":"5","author":"Gack","year":"2009","journal-title":"Cell Host Microbe"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1038\/s41467-018-04214-8","article-title":"Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition","volume":"9","author":"Koliopoulos","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1128\/JVI.01265-06","article-title":"Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus","volume":"81","author":"Mibayashi","year":"2007","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1128\/JVI.01956-12","article-title":"Toll-like receptor expression and induction of type I and type III interferons in primary airway epithelial cells","volume":"87","author":"Ioannidis","year":"2013","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"498","DOI":"10.3389\/fimmu.2016.00498","article-title":"Viral Evasion Strategies in Type I IFN Signaling\u2014A Summary of Recent Developments","volume":"7","author":"Schulz","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"20059","DOI":"10.1074\/jbc.R700016200","article-title":"JAK-STAT signaling: From interferons to cytokines","volume":"282","author":"Schindler","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4123","DOI":"10.1128\/JVI.03644-13","article-title":"Effects of aging on influenza virus infection dynamics","volume":"88","author":"Wilk","year":"2014","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.4049\/jimmunol.0901022","article-title":"Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response","volume":"184","author":"Panda","year":"2010","journal-title":"J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.coi.2014.03.008","article-title":"Immunosenescence: Influenza vaccination and the elderly","volume":"29","author":"Haq","year":"2014","journal-title":"Curr. Opin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0047-6374(96)01855-6","article-title":"Cytokines and impaired CD8+ CTL activity among elderly persons and the enhancing effect of IL-12","volume":"94","author":"Mbawuike","year":"1997","journal-title":"Mech. Ageing Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1086\/600383","article-title":"Viral loads and duration of viral shedding in adult patients hospitalized with influenza","volume":"200","author":"Lee","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.clim.2013.02.022","article-title":"An altered relationship of influenza vaccine-specific IgG responses with T cell immunity occurs with aging in humans","volume":"147","author":"Kang","year":"2013","journal-title":"Clin. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1086\/516788","article-title":"Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults","volume":"195","author":"Allore","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/imr.12864","article-title":"Age-related factors that affect B cell responses to vaccination in mice and humans","volume":"296","author":"Frasca","year":"2020","journal-title":"Immunol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"110857","DOI":"10.1016\/j.exger.2020.110857","article-title":"Strain specificities in influence of ageing on germinal centre reaction to inactivated influenza virus antigens in mice: Sex-based differences","volume":"133","author":"Bufan","year":"2020","journal-title":"Exp. Gerontol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"286","DOI":"10.4110\/in.2016.16.5.286","article-title":"Enhanced Viral Replication by Cellular Replicative Senescence","volume":"16","author":"Kim","year":"2016","journal-title":"Immune Netw."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.exger.2014.11.005","article-title":"Aging disturbs the balance between effector and regulatory CD4+ T cells","volume":"60","author":"Abdulahad","year":"2014","journal-title":"Exp. Gerontol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1126\/scisignal.aan2392","article-title":"Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes","volume":"10","author":"Molony","year":"2017","journal-title":"Sci. Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/1465-9921-10-112","article-title":"Impaired immune responses in the lungs of aged mice following influenza infection","volume":"10","author":"Toapanta","year":"2009","journal-title":"Respir. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00395-17","DOI":"10.1128\/JVI.00395-17","article-title":"Discrete Dynamical Modeling of Influenza Virus Infection Suggests Age-Dependent Differences in Immunity","volume":"91","author":"Keef","year":"2017","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5274","DOI":"10.3390\/v7102875","article-title":"Modeling Influenza Virus Infection: A Roadmap for Influenza Research","volume":"7","author":"Boianelli","year":"2015","journal-title":"Viruses"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1016\/S0264-410X(98)00133-9","article-title":"Responses to influenza vaccination in different T-cell subsets: A comparison of healthy young and older adults","volume":"16","author":"McElhaney","year":"1998","journal-title":"Vaccine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s11357-010-9191-3","article-title":"Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity","volume":"33","author":"Sridharan","year":"2011","journal-title":"Age"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"673","DOI":"10.4049\/jimmunol.173.1.673","article-title":"Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine","volume":"173","author":"Kang","year":"2004","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.mad.2004.07.001","article-title":"Age-associated changes in the frequency of naive, memory and effector CD8+ T cells","volume":"125","author":"Hong","year":"2004","journal-title":"Mech. Ageing Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.mad.2011.08.005","article-title":"Natural killer cell function is altered during the primary response of aged mice to influenza infection","volume":"132","author":"Beli","year":"2011","journal-title":"Mech. Ageing Dev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.mad.2008.01.003","article-title":"Characterization of age-related changes in natural killer cells during primary influenza infection in mice","volume":"129","author":"Nogusa","year":"2008","journal-title":"Mech. Ageing Dev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1159\/000350536","article-title":"Mechanisms and implications of age-associated impaired innate interferon secretion by dendritic cells: A mini-review","volume":"59","author":"Agrawal","year":"2013","journal-title":"Gerontology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1007\/s11357-012-9477-8","article-title":"Impaired secretion of interferons by dendritic cells from aged subjects to influenza: Role of histone modifications","volume":"35","author":"Prakash","year":"2013","journal-title":"Age"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cellimm.2004.07.001","article-title":"Impaired antigen-induced CD8+ T cell clonal expansion in aging is due to defects in antigen presenting cell function","volume":"229","author":"Plowden","year":"2004","journal-title":"Cell. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"358","DOI":"10.14336\/AD.2017.0701","article-title":"Aged Mice are More Resistant to Influenza Virus Infection due to Reduced Inflammation and Lung Pathology","volume":"9","author":"Lu","year":"2018","journal-title":"Aging Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"164309","DOI":"10.1155\/2014\/164309","article-title":"Powering the immune system: Mitochondria in immune function and deficiency","volume":"2014","author":"Walker","year":"2014","journal-title":"J. Immunol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.immuni.2015.02.002","article-title":"Mitochondria in the regulation of innate and adaptive immunity","volume":"42","author":"Weinberg","year":"2015","journal-title":"Immunity"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/ni.3704","article-title":"Mitochondria are the powerhouses of immunity","volume":"18","author":"Mills","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Lei, Y., Moore, C.B., Liesman, R.M., O\u2019Connor, B.P., Bergstralh, D.T., Chen, Z.J., Pickles, R.J., and Ting, J.P. (2009). MAVS-mediated apoptosis and its inhibition by viral proteins. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005466"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Sun, X., Nie, X., Sun, L., Tang, T.S., Chen, D., and Sun, Q. (2012). COX5B regulates MAVS-mediated antiviral signaling through interaction with ATG5 and repressing ROS production. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1003086"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1074\/jbc.M113.469239","article-title":"Inhibition of p38 mitogen-activated protein kinase impairs influenza virus-induced primary and secondary host gene responses and protects mice from lethal H5N1 infection","volume":"289","author":"Borgeling","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11359","DOI":"10.1128\/JVI.00804-10","article-title":"Toll-like receptor 4-mediated activation of p38 mitogen-activated protein kinase is a determinant of respiratory virus entry and tropism","volume":"84","author":"Marchant","year":"2010","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4068","DOI":"10.1096\/fj.10-158766","article-title":"MAP kinase-activated protein kinases 2 and 3 are required for influenza A virus propagation and act via inhibition of PKR","volume":"24","author":"Luig","year":"2010","journal-title":"FASEB J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e2287","DOI":"10.21769\/BioProtoc.2287","article-title":"Murine Bronchoalveolar Lavage","volume":"7","author":"Sun","year":"2017","journal-title":"Bio-Protoc."},{"key":"ref_50","first-page":"149","article-title":"Agarose infiltration improves morphology of cryostat sections of lung","volume":"71","author":"Halbower","year":"1994","journal-title":"Lab. Investig."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12097\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:27:53Z","timestamp":1760167673000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12097"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,9]]},"references-count":50,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222212097"],"URL":"https:\/\/doi.org\/10.3390\/ijms222212097","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,9]]}}}