{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:19:03Z","timestamp":1790680743501,"version":"4.1.0"},"reference-count":120,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T00:00:00Z","timestamp":1619568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["206579\/Z\/17\/Z"],"award-info":[{"award-number":["206579\/Z\/17\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI147172"],"award-info":[{"award-number":["R21AI147172"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Infection with influenza A and B viruses results in a mild to severe respiratory tract infection. It is widely accepted that many factors affect the severity of influenza disease, including viral replication, host adaptation, innate immune signalling, pre-existing immunity, and secondary infections. In this review, we will focus on the interplay between influenza virus RNA synthesis and the detection of influenza virus RNA by our innate immune system. Specifically, we will discuss the generation of various RNA species, host pathogen receptors, and host shut-off. In addition, we will also address outstanding questions that currently limit our knowledge of influenza virus replication and host adaption. Understanding the molecular mechanisms underlying these factors is essential for assessing the pandemic potential of future influenza virus outbreaks.<\/jats:p>","DOI":"10.3390\/v13050780","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T22:29:07Z","timestamp":1619648947000},"page":"780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Influenza Virus RNA Synthesis and the Innate Immune Response"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4800-9453","authenticated-orcid":false,"given":"Sabrina","family":"Weis","sequence":"first","affiliation":[{"name":"Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aartjan J. W.","family":"te Velthuis","sequence":"additional","affiliation":[{"name":"Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms5816","article-title":"Conserved and host-specific features of influenza virion architecture","volume":"5","author":"Hutchinson","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tong, S., Zhu, X., Li, Y., Shi, M., Zhang, J., Bourgeois, M., Yang, H., Chen, X., Recuenco, S., and Gomez, J. (2013). New World Bats Harbor Diverse Influenza A Viruses. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003657"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a038398","DOI":"10.1101\/cshperspect.a038398","article-title":"Structure and Function of the Influenza Virus Transcription and Replication Machinery","volume":"10","author":"Fodor","year":"2020","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/0378-1119(80)90007-4","article-title":"The 3\u2019 and 5\u2019-terminal sequences of influenza A, B and C virus RNA segments are highly conserved and show partial inverted complementarity","volume":"8","author":"Desselberger","year":"1980","journal-title":"Gene"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4092","DOI":"10.1128\/jvi.68.6.4092-4096.1994","article-title":"The influenza virus panhandle is involved in the initiation of transcription","volume":"68","author":"Fodor","year":"1994","journal-title":"J. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","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":"Fodor","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41579-020-00501-8","article-title":"Structural insights into RNA polymerases of negative-sense RNA viruses","volume":"19","author":"Grimes","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Krischuns, T., Lukarska, M., Naffakh, N., and Cusack, S. (2021). Influenza Virus RNA-Dependent RNA Polymerase and the Host Transcriptional Apparatus. Annu. Rev. Biochem., 90.","DOI":"10.1146\/annurev-biochem-072820-100645"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.cell.2020.03.061","article-title":"A Structure-Based Model for the Complete Transcription Cycle of Influenza Polymerase","volume":"181","author":"Wandzik","year":"2020","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3473","DOI":"10.1128\/JVI.73.4.3473-3476.1999","article-title":"Direct evidence that the poly(A) tail of influenza A virus mRNA is synthesized by reiterative copying of a U track in the virion RNA template","volume":"73","author":"Poon","year":"1999","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E4238","DOI":"10.1073\/pnas.1315068110","article-title":"Isolation and characterization of the positive-sense replicative intermediate of a negative-strand RNA virus","volume":"110","author":"York","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1261\/rna.045369.114","article-title":"Comparative mutational analyses of influenza A viruses","volume":"21","author":"Cheung","year":"2014","journal-title":"RNA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"187","DOI":"10.20506\/rst.28.1.1879","article-title":"Pandemic influenza\u2014Including a risk assessment of H5N1","volume":"28","author":"Taubenberger","year":"2009","journal-title":"Rev. Sci. Tech. l\u2019OIE"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.chom.2010.05.009","article-title":"Influenza Virus Evolution, Host Adaptation, and Pandemic Formation","volume":"7","author":"Taubenberger","year":"2010","journal-title":"Cell Host. Microbe"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1172\/JCI44947","article-title":"Virulence determinants of pandemic influenza viruses","volume":"121","author":"Tscherne","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1038\/nm1477","article-title":"Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia","volume":"12","author":"Simmons","year":"2006","journal-title":"Nat. Med."},{"key":"ref_17","first-page":"319","article-title":"Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus","volume":"445","author":"Kobasa","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_18","first-page":"578","article-title":"Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus","volume":"443","author":"Kash","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Arankalle, V.A., Lole, K.S., Arya, R.P., Tripathy, A.S., Ramdasi, A.Y., Chadha, M.S., Sangle, S.A., and Kadam, D.B. (2010). Role of Host Immune Response and Viral Load in the Differential Outcome of Pandemic H1N1 (2009) Influenza Virus Infection in Indian Patients. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013099"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1099\/vir.0.030346-0","article-title":"Cytokine production by primary human macrophages infected with highly pathogenic H5N1 or pandemic H1N1 2009 influenza viruses","volume":"92","author":"Sakabe","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/s41564-018-0240-5","article-title":"Mini viral RNAs act as innate immune agonists during influenza virus infection","volume":"3","author":"Velthuis","year":"2018","journal-title":"Nat. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1126\/science.1222213","article-title":"An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response","volume":"337","author":"Jagger","year":"2012","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9263","DOI":"10.1128\/JVI.01205-16","article-title":"Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity","volume":"90","author":"Turnbull","year":"2016","journal-title":"J. Virol."},{"key":"ref_24","first-page":"355","article-title":"Structure of influenza A polymerase bound to the viral RNA promoter","volume":"516","author":"Pflug","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_25","first-page":"361","article-title":"Structural insight into cap-snatching and RNA synthesis by influenza polymerase","volume":"516","author":"Reich","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_26","first-page":"114","article-title":"Crystal structure of the RNA-dependent RNA polymerase from influenza C virus","volume":"527","author":"Hengrung","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/j.molcel.2014.12.031","article-title":"Cryo-EM Structure of Influenza Virus RNA Polymerase Complex at 4.3 \u00c5 Resolution","volume":"57","author":"Chang","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.virusres.2017.01.013","article-title":"Structural insights into RNA synthesis by the influenza virus transcription-replication machine","volume":"234","author":"Pflug","year":"2017","journal-title":"Virus Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4403","DOI":"10.1007\/s00018-014-1695-z","article-title":"Common and unique features of viral RNA-dependent polymerases","volume":"71","year":"2014","journal-title":"Cell Mol. Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nmicrobiol.2016.29","article-title":"The role of the priming loop in influenza A virus RNA synthesis","volume":"1","author":"Velthuis","year":"2016","journal-title":"Nat. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e01773-17","DOI":"10.1128\/JVI.01773-17","article-title":"A Mechanism for Priming and Realignment during Influenza A Virus Replication","volume":"92","author":"Oymans","year":"2017","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Velthuis, A.J.W.T., and Oymans, J. (2017). Initiation, Elongation, and Realignment during Influenza Virus mRNA Synthesis. J. Virol., 92.","DOI":"10.1101\/197210"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e02467-16","DOI":"10.1128\/JVI.02467-16","article-title":"Role of the PB2 627 Domain in Influenza A Virus Polymerase Function","volume":"91","author":"Nilsson","year":"2017","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6466","DOI":"10.1093\/nar\/gkz313","article-title":"Real-time analysis of single influenza virus replication complexes reveals large promoter-dependent differences in initiation dynamics","volume":"47","author":"Robb","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_35","first-page":"10304","article-title":"Single-molecule FRET reveals the pre-initiation and initiation conformations of influenza virus promoter RNA","volume":"44","author":"Robb","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","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":"ref_37","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1126\/science.1228172","article-title":"The Structure of Native Influenza Virion Ribonucleoproteins","volume":"338","author":"Arranz","year":"2012","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1093\/embo-reports\/kve063","article-title":"Three-dimensional reconstruction of a recombinant influenza virus ribonucleoprotein particle","volume":"2","author":"Area","year":"2001","journal-title":"EMBO Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1093\/emboj\/16.6.1248","article-title":"Roles of the influenza virus polymerase and nucleoprotein in forming a functional RNP structure","volume":"16","author":"Klumpp","year":"1997","journal-title":"EMBO J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41564-020-0675-3","article-title":"Structural insights into influenza A virus ribonucleoproteins reveal a processive helical track as transcription mechanism","volume":"5","author":"Coloma","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4144","DOI":"10.1093\/nar\/gkab203","article-title":"Crystal structures of influenza nucleoprotein complexed with nucleic acid provide insights into the mechanism of RNA interaction","volume":"49","author":"Tang","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1038\/s41564-019-0513-7","article-title":"The structure of the influenza A virus genome","volume":"4","author":"Dadonaite","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/0092-8674(81)90449-9","article-title":"A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription","volume":"23","author":"Plotch","year":"1981","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5812","DOI":"10.1128\/JVI.79.9.5812-5818.2005","article-title":"Association of the Influenza A Virus RNA-Dependent RNA Polymerase with Cellular RNA Polymerase II","volume":"79","author":"Engelhardt","year":"2005","journal-title":"J. Virol."},{"key":"ref_45","first-page":"117","article-title":"Structural basis of an essential interaction between influenza polymerase and Pol II CTD","volume":"541","author":"Lukarska","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.molcel.2018.05.011","article-title":"A Mechanism for the Activation of the Influenza Virus Transcriptase","volume":"70","author":"Martin","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.tim.2018.12.013","article-title":"Interplay between Influenza Virus and the Host RNA Polymerase II Transcriptional Machinery","volume":"27","author":"Walker","year":"2019","journal-title":"Trends Microbiol."},{"key":"ref_48","first-page":"914","article-title":"The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit","volume":"458","author":"Dias","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5052","DOI":"10.1093\/nar\/gkv333","article-title":"Sequencing the cap-snatching repertoire of H1N1 influenza provides insight into the mechanism of viral transcription initiation","volume":"43","author":"Koppstein","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep06181","article-title":"Deep sequencing reveals the eight facets of the influenza A\/HongKong\/1\/1968 (H3N2) virus cap-snatching process","volume":"4","author":"Sikora","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/s41594-019-0232-z","article-title":"Structural snapshots of actively transcribing influenza polymerase","volume":"26","author":"Kouba","year":"2019","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.virol.2019.08.002","article-title":"Priming and realignment by the influenza a virus RdRp is dependent on the length of the host primers and the extent of base pairing to viral RNA","volume":"536","author":"Sikora","year":"2019","journal-title":"Virology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1016\/j.cell.2020.05.035","article-title":"Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection","volume":"181","author":"Ho","year":"2020","journal-title":"Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.4161\/rna.25356","article-title":"Biogenesis, assembly, and export of viral messenger ribonucleoproteins in the influenza A virus infected cell","volume":"10","author":"York","year":"2013","journal-title":"RNA Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1128\/JVI.80.5.2337-2348.2006","article-title":"Different De Novo Initiation Strategies Are Used by Influenza Virus RNA Polymerase on Its cRNA and Viral RNA Promoters during Viral RNA Replication","volume":"80","author":"Deng","year":"2006","journal-title":"J. Virol."},{"key":"ref_56","first-page":"638","article-title":"Host ANP32A mediates the assembly of the influenza virus replicase","volume":"587","author":"Carrique","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Chen, K.-Y., Afonso, E.D.S., Enouf, V., Isel, C., and Naffakh, N. (2019). Influenza virus polymerase subunits co-evolve to ensure proper levels of dimerization of the heterotrimer. PLOS Pathog., 15.","DOI":"10.1371\/journal.ppat.1008034"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6263","DOI":"10.1128\/JVI.78.12.6263-6270.2004","article-title":"Mutational Analysis of the Influenza Virus cRNA Promoter and Identification of Nucleotides Critical for Replication","volume":"78","author":"Crow","year":"2004","journal-title":"J. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.molcel.2015.11.016","article-title":"Influenza Polymerase Can Adopt an Alternative Configuration Involving a Radical Repacking of PB2 Domains","volume":"61","author":"Thierry","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_60","first-page":"287","article-title":"Structures of influenza A virus RNA polymerase offer insight into viral genome replication","volume":"573","author":"Fan","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1038\/s41564-019-0487-5","article-title":"Structural insight into RNA synthesis by influenza D polymerase","volume":"4","author":"Peng","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Jorba, N., Coloma, R., and Ort\u00edn, J. (2009). Genetic trans-Complementation Establishes a New Model for Influenza Virus RNA Transcription and Replication. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000462"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"11525","DOI":"10.1073\/pnas.1001984107","article-title":"Influenza A virus-generated small RNAs regulate the switch from transcription to replication","volume":"107","author":"Perez","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1146\/annurev.mi.34.100180.003155","article-title":"Defective interfering influenza viruses","volume":"34","author":"Nayak","year":"1980","journal-title":"Ann. Rev. Microbiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms2589","article-title":"The role and assembly mechanism of nucleoprotein in influenza A virus ribonucleoprotein complexes","volume":"4","author":"Turrell","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Koire, A., Gilbert, B.E., Sucgang, R., and Zechiedrich, L. (2016). Repurposed Transcriptomic Data Reveal Small Viral RNA Produced by Influenza Virus during Infection in Mice. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165729"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"8064","DOI":"10.1128\/JVI.00240-13","article-title":"Sequence Analysis of In Vivo Defective Interfering-Like RNA of Influenza A H1N1 Pandemic Virus","volume":"87","author":"Saira","year":"2013","journal-title":"J. Virol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5217","DOI":"10.1128\/JVI.03193-13","article-title":"Defective Interfering Influenza Virus RNAs: Time to Reevaluate Their Clinical Potential as Broad-Spectrum Antivirals?","volume":"88","author":"Dimmock","year":"2014","journal-title":"J. Virol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4632","DOI":"10.1128\/JVI.00014-14","article-title":"An Unbiased Genetic Screen Reveals the Polygenic Nature of the Influenza Virus Anti-Interferon Response","volume":"88","author":"Killip","year":"2014","journal-title":"J. Virol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Russell, A.B., Elshina, E., Kowalsky, J.R., Te Velthuis, A.J., and Bloom, J.D. (2019). Single-Cell Virus Sequencing of Influenza Infections that Trigger Innate Immunity. J. Virol., 93.","DOI":"10.1128\/JVI.00500-19"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1126\/science.aan8806","article-title":"Genome-wide identification of interferon-sensitive mutations enables influenza vaccine design","volume":"359","author":"Du","year":"2018","journal-title":"Science"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Nilsson-Payant, B.E., Blanco-Melo, D., Uhl, S., Escudero-P\u00e9rez, B., Olschewski, S., Thibault, P., Panis, M., Rosenthal, M., Mu\u00f1oz-Fontela, C., and Lee, B. (2021). Reduced Nucleoprotein availability impairs negative-sense RNA virus replication and promotes host recognition. J. Virol., 95.","DOI":"10.1128\/JVI.02274-20"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Liu, G., Lu, Y., Liu, Q., and Zhou, Y. (2019). Inhibition of Ongoing Influenza A Virus Replication Reveals Different Mechanisms of RIG-I Activation. J. Virol., 93.","DOI":"10.1128\/JVI.02066-18"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Alnaji, F.G., and Brooke, C.B. (2020). Influenza virus DI particles: Defective interfering or delightfully interesting?. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008436"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/0092-8674(82)90348-8","article-title":"Nucleotide sequences of influenza virus segments 1 and 3 reveal mosaic structure of a small viral RNA segment","volume":"28","author":"Fields","year":"1982","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Alnaji, F.G., Holmes, J.R., Rendon, G., Vera, J.C., Fields, C.J., Martin, B.E., and Brooke, C.B. (2019). Sequencing Framework for the Sensitive Detection and Precise Mapping of Defective Interfering Particle-Associated Deletions across Influenza A and B Viruses. J. Virol., 93.","DOI":"10.1128\/JVI.00354-19"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1261\/rna.077529.120","article-title":"RNA-seq accuracy and reproducibility for the mapping and quantification of influenza defective viral genomes","volume":"26","author":"Boussier","year":"2020","journal-title":"RNA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/0092-8674(83)90394-X","article-title":"Does the higher order structure of the influenza virus ribonucleoprotein guide sequence rearrangements in influenza viral RNA?","volume":"34","author":"Jennings","year":"1983","journal-title":"Cell"},{"key":"ref_79","doi-asserted-by":"crossref","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":"ref_80","doi-asserted-by":"crossref","unstructured":"Malik, G., and Zhou, Y. (2020). Innate Immune Sensing of Influenza a Virus. Viruses, 12.","DOI":"10.3390\/v12070755"},{"key":"ref_81","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_82","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1097\/QCO.0b013e328344c0e3","article-title":"Innate immune response to influenza virus","volume":"24","author":"Wu","year":"2011","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/s41577-020-0288-3","article-title":"RIG-I-like receptors: Their regulation and roles in RNA sensing","volume":"20","author":"Rehwinkel","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_84","first-page":"1","article-title":"Nuclear-resident RIG-I senses viral replication inducing antiviral immunity","volume":"9","author":"Liu","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1261\/rna.035949.112","article-title":"A structure-based model of RIG-I activation","volume":"18","author":"Kolakofsky","year":"2012","journal-title":"RNA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1016\/j.celrep.2019.11.052","article-title":"RIG-I Recognition of RNA Targets: The Influence of Terminal Base Pair Sequence and Overhangs on Affinity and Signaling","volume":"29","author":"Ren","year":"2019","journal-title":"Cell Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.mib.2014.05.011","article-title":"Sensing viral invasion by RIG-I like receptors","volume":"20","author":"Yoo","year":"2014","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_88","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_89","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nri2975","article-title":"Mitochondria in innate immune responses","volume":"11","author":"West","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.cell.2005.08.012","article-title":"Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-\u03baB and IRF3","volume":"122","author":"Seth","year":"2005","journal-title":"Cell"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3420","DOI":"10.1128\/JVI.02623-08","article-title":"MAVS Self-Association Mediates Antiviral Innate Immune Signaling","volume":"83","author":"Tang","year":"2009","journal-title":"J. Virol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/embor.2009.258","article-title":"Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway","volume":"11","author":"Castanier","year":"2010","journal-title":"EMBO Rep."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"ra7","DOI":"10.1126\/scisignal.2001147","article-title":"Mitochondrial Membrane Potential Is Required for MAVS-Mediated Antiviral Signaling","volume":"4","author":"Koshiba","year":"2011","journal-title":"Sci. Signal."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"8729","DOI":"10.1128\/JVI.01384-16","article-title":"The PB2 Subunit of the Influenza A Virus RNA Polymerase Is Imported into the Mitochondrial Matrix","volume":"90","author":"Long","year":"2016","journal-title":"J. Virol."},{"key":"ref_95","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_96","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms5713","article-title":"Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity","volume":"5","author":"Yoshizumi","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Cheung, P.-H.H., Lee, T.-W.T., Kew, C., Chen, H., Yuen, K.-Y., Chan, C.-P., and Jin, D.-Y. (2020). Virus subtype-specific suppression of MAVS aggregation and activation by PB1-F2 protein of influenza A (H7N9) virus. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008611"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Varga, Z.T., Ramos, I., Hai, R., Schmolke, M., Garc\u00eda-Sastre, A., Fernandez-Sesma, A., and Palese, P. (2011). The Influenza Virus Protein PB1-F2 Inhibits the Induction of Type I Interferon at the Level of the MAVS Adaptor Protein. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002067"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Nogales, A., Martinez-Sobrido, L., Topham, D.J., and DeDiego, M.L. (2018). Modulation of Innate Immune Responses by the Influenza A NS1 and PA-X Proteins. Viruses, 10.","DOI":"10.3390\/v10120708"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.it.2017.11.002","article-title":"ZBP1: Innate Sensor Regulating Cell Death and Inflammation","volume":"39","author":"Kuriakose","year":"2018","journal-title":"Trends Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.cell.2020.02.050","article-title":"Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis","volume":"180","author":"Zhang","year":"2020","journal-title":"Cell"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1126\/science.1132505","article-title":"5\u2019-Triphosphate RNA Is the Ligand for RIG-I","volume":"314","author":"Hornung","year":"2006","journal-title":"Science"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1016\/j.str.2010.05.007","article-title":"The Structural Basis of 5\u2032 Triphosphate Double-Stranded RNA Recognition by RIG-I C-Terminal Domain","volume":"18","author":"Lu","year":"2010","journal-title":"Structure"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.immuni.2009.05.008","article-title":"Recognition of 5\u2032 Triphosphate by RIG-I Helicase Requires Short Blunt Double-Stranded RNA as Contained in Panhandle of Negative-Strand Virus","volume":"31","author":"Schlee","year":"2009","journal-title":"Immunity"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"12067","DOI":"10.1073\/pnas.0900971106","article-title":"5\u2019-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I","volume":"106","author":"Schmidt","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e1701854","DOI":"10.1126\/sciadv.1701854","article-title":"A minimal RNA ligand for potent RIG-I activation in living mice","volume":"4","author":"Linehan","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_107","first-page":"523","article-title":"Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA","volume":"454","author":"Saito","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"16303","DOI":"10.1073\/pnas.1005077107","article-title":"Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing","volume":"107","author":"Baum","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.cell.2011.09.039","article-title":"Structural Basis for the Activation of Innate Immune Pattern-Recognition Receptor RIG-I by Viral RNA","volume":"147","author":"Kowalinski","year":"2011","journal-title":"Cell"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.cell.2010.01.020","article-title":"RIG-I Detects Viral Genomic RNA during Negative-Strand RNA Virus Infection","volume":"140","author":"Rehwinkel","year":"2010","journal-title":"Cell"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5645","DOI":"10.1038\/ncomms6645","article-title":"Viral suppressors of the RIG-I-mediated interferon response are pre-packaged in influenza virions","volume":"5","author":"Liedmann","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3942","DOI":"10.1128\/JVI.03109-13","article-title":"Activation of the Interferon Induction Cascade by Influenza A Viruses Requires Viral RNA Synthesis and Nuclear Export","volume":"88","author":"Killip","year":"2014","journal-title":"J. Virol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.virusres.2015.02.003","article-title":"Influenza virus activation of the interferon system","volume":"209","author":"Killip","year":"2015","journal-title":"Virus Res."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Tapia, K., Kim, W.-K., Sun, Y., Mercado-L\u00f3pez, X., Dunay, E., Wise, M., Adu, M., and L\u00f3pez, C.B. (2013). Defective Viral Genomes Arising In Vivo Provide Critical Danger Signals for the Triggering of Lung Antiviral Immunity. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003703"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Levene, R.E., and Gaglia, M.M. (2018). Host Shutoff in Influenza A Virus: Many Means to an End. Viruses, 10.","DOI":"10.3390\/v10090475"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/s41594-018-0124-7","article-title":"Influenza virus infection causes global RNAPII termination defects","volume":"25","author":"Zhao","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Chaimayo, C., Dunagan, M., Hayashi, T., Santoso, N., and Takimoto, T. (2018). Specificity and functional interplay between influenza virus PA-X and NS1 shutoff activity. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007465"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.virol.2017.06.020","article-title":"Influenza A virus cap-snatches host RNAs based on their abundance early after infection","volume":"509","author":"Sikora","year":"2017","journal-title":"Virology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1016\/j.celrep.2018.04.047","article-title":"Influenza Virus Mounts a Two-Pronged Attack on Host RNA Polymerase II Transcription","volume":"23","author":"Bauer","year":"2018","journal-title":"Cell Rep."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41590-017-0005-y","article-title":"Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity","volume":"19","author":"Chiang","year":"2018","journal-title":"Nat. Immunol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/5\/780\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:54:31Z","timestamp":1760162071000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/5\/780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,28]]},"references-count":120,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["v13050780"],"URL":"https:\/\/doi.org\/10.3390\/v13050780","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,28]]}}}