{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:00:13Z","timestamp":1790517613411,"version":"4.1.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T00:00:00Z","timestamp":1595203200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T00:00:00Z","timestamp":1595203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Major 5\u2032terminally deleted (5\u2032TD) group-B enterovirus (EV-B) populations were identified in heart biopsies of patients with fulminant myocarditis or dilated cardiomyopathy suggesting that these 5\u2032TD forms are key drivers of host-cell interaction in EV cardiac infections. To date, early emergence of EV-B 5\u2032TD forms and its impact on type 1 IFN response during acute myocarditis remains unknown. Using quantitative RACE-PCR assay, we identified major EV-B 5\u2032TD RNA populations in plasma or heart samples of acute myocarditis cases. Deletions identified within the 5\u2032 non-coding region of EV-B populations only affected secondary-structural elements of genomic RNA domain I and were distinguished in two major groups based on the extent of RNA structural deletions. Proportions of these two respective EV-B 5\u2032TD population groups were positively or negatively correlated with IFN-\u03b2 levels in plasma samples of myocarditis patients. Transfection of synthetic CVB3\/28 RNAs harboring various 5\u2032terminal full-length or deleted sequences into human cultured cardiomyocytes demonstrated that viral genomic RNA domain I possessed essential immunomodulatory secondary-structural elements responsible for IFN-\u03b2 pathway induction. Overall, our results highlight the early emergence of major EVB-TD populations which deletions affecting secondary\u2013structures of RNA domain I can modulate innate immune sensing mechanisms in cardiomyocytes of patients with acute myocarditis.<\/jats:p>","DOI":"10.1038\/s41598-020-67648-5","type":"journal-article","created":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T10:04:16Z","timestamp":1595239456000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Major 5\u2032terminally deleted enterovirus populations modulate type I IFN response in acute myocarditis patients and in human cultured cardiomyocytes"],"prefix":"10.1038","volume":"10","author":[{"given":"M.","family":"Glenet","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"N\u2019Guyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Mirand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Henquell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.-L.","family":"Lebreil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Berri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Bani-Sadr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Lina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Schuffenecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Andreoletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The French Enterovirus Myocarditis Study Group (FEMSG)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Mirand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Henquell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Laure","family":"Mathieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellia","family":"Mezgueldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Verdan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Motreff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Lina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Schuffenecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira","family":"Fafi-Kremer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Lepiller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Bruneval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,20]]},"reference":[{"key":"67648_CR1","doi-asserted-by":"publisher","first-page":"2073","DOI":"10.1093\/eurheartj\/ehn296","volume":"29","author":"R Dennert","year":"2008","unstructured":"Dennert, R., Crijns, H. J. & Heymans, S. Acute viral myocarditis. Eur. Heart J.29, 2073\u20132082 (2008).","journal-title":"Eur. Heart J."},{"key":"67648_CR2","unstructured":"Pallansch, M. A. & Roos, R. Enteroviruses\u202f: Polioviruses, Coxsackieviruses, Echoviruses, and Newer Enteroviruses. In Fields Virology Vol. 1 840\u2013893 (Lippincott William & Wilkens Company, 2007)."},{"key":"67648_CR3","unstructured":"Racaniello, V. R. Picornaviridae: the viruses and their replication. In Fields Virology Vol. 1 795\u2013838 (Knipe & Howley, 2007)."},{"key":"67648_CR4","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1016\/j.virol.2008.02.030","volume":"375","author":"NM Chapman","year":"2008","unstructured":"Chapman, N. M., Kim, K.-S., Drescher, K. M., Oka, K. & Tracy, S. 5\u2019 terminal deletions in the genome of a coxsackievirus B2 strain occurred naturally in human heart. Virology375, 480\u2013491 (2008).","journal-title":"Virology"},{"key":"67648_CR5","doi-asserted-by":"publisher","first-page":"7024","DOI":"10.1128\/JVI.79.11.7024-7041.2005","volume":"79","author":"K-S Kim","year":"2005","unstructured":"Kim, K.-S. et al. 5\u2019-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA. J. Virol.79, 7024\u20137041 (2005).","journal-title":"J. Virol."},{"key":"67648_CR6","doi-asserted-by":"publisher","first-page":"2033","DOI":"10.1128\/JVI.01774-07","volume":"82","author":"K-S Kim","year":"2008","unstructured":"Kim, K.-S., Chapman, N. M. & Tracy, S. Replication of coxsackievirus B3 in primary cell cultures generates novel viral genome deletions. J. Virol.82, 2033\u20132037 (2008).","journal-title":"J. Virol."},{"key":"67648_CR7","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.3201\/eid2208.160186","volume":"22","author":"A Bouin","year":"2016","unstructured":"Bouin, A. et al. Major persistent 5\u2032 terminally deleted coxsackievirus B3 populations in human endomyocardial tissues. Emerg. Infect. Dis.22, 1488\u20131490 (2016).","journal-title":"Emerg. Infect. Dis."},{"key":"67648_CR8","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1161\/CIRCULATIONAHA.118.035966","volume":"139","author":"A Bouin","year":"2019","unstructured":"Bouin, A. et al. Enterovirus persistence in cardiac cells of patients with idiopathic dilated cardiomyopathy is linked to 5\u2019 terminal genomic RNA-deleted viral populations with viral-encoded proteinase activities. Circulation139, 2326\u20132338 (2019).","journal-title":"Circulation"},{"key":"67648_CR9","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1016\/j.celrep.2012.10.005","volume":"2","author":"Q Feng","year":"2012","unstructured":"Feng, Q. et al. MDA5 detects the double-stranded RNA replicative form in picornavirus-infected cells. Cell Rep.2, 1187\u20131196 (2012).","journal-title":"Cell Rep."},{"key":"67648_CR10","doi-asserted-by":"publisher","first-page":"e95927","DOI":"10.1371\/journal.pone.0095927","volume":"9","author":"Q Feng","year":"2014","unstructured":"Feng, Q. et al. Coxsackievirus cloverleaf RNA containing a 5\u2032 triphosphate triggers an antiviral response via RIG-I activation. PLoS ONE9, e95927 (2014).","journal-title":"PLoS ONE"},{"key":"67648_CR11","doi-asserted-by":"crossref","unstructured":"L\u00e9v\u00eaque, N. et al. Functional Consequences of RNA 5\u2032-Terminal Deletions on Coxsackievirus B3 RNA Replication and Ribonucleoprotein Complex Formation. J. Virol.91, (2017).","DOI":"10.1128\/JVI.00423-17"},{"key":"67648_CR12","doi-asserted-by":"publisher","first-page":"4229","DOI":"10.1128\/JVI.02198-09","volume":"84","author":"KJ Ertel","year":"2010","unstructured":"Ertel, K. J., Brunner, J. E. & Semler, B. L. Mechanistic consequences of hnRNP C binding to both RNA termini of poliovirus negative-strand RNA intermediates. J. Virol.84, 4229\u20134242 (2010).","journal-title":"J. Virol."},{"key":"67648_CR13","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.virol.2010.01.031","volume":"400","author":"JE Brunner","year":"2010","unstructured":"Brunner, J. E., Ertel, K. J., Rozovics, J. M. & Semler, B. L. Delayed kinetics of poliovirus RNA synthesis in a human cell line with reduced levels of hnRNP C proteins. Virology400, 240\u2013247 (2010).","journal-title":"Virology"},{"key":"67648_CR14","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.virol.2016.05.021","volume":"496","author":"L Jaramillo","year":"2016","unstructured":"Jaramillo, L., Smithee, S., Tracy, S. & Chapman, N. M. Domain I of the 5\u2032 non-translated genomic region in coxsackievirus B3 RNA is not required for productive replication. Virology496, 127\u2013130 (2016).","journal-title":"Virology"},{"key":"67648_CR15","doi-asserted-by":"crossref","unstructured":"Reikine, S., Nguyen, J. B. & Modis, Y. Pattern recognition and signaling mechanisms of RIG-I and MDA5. Fronti Immunol.5, (2014).","DOI":"10.3389\/fimmu.2014.00342"},{"key":"67648_CR16","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1161\/CIRCRESAHA.115.306573","volume":"118","author":"G Fung","year":"2016","unstructured":"Fung, G., Luo, H., Qiu, Y., Yang, D. & McManus, B. Myocarditis. Circ. Res.118, 496\u2013514 (2016).","journal-title":"Circ. Res."},{"key":"67648_CR17","doi-asserted-by":"publisher","first-page":"e00423","DOI":"10.1128\/JVI.00423-17","volume":"91","author":"N L\u00e9v\u00eaque","year":"2017","unstructured":"L\u00e9v\u00eaque, N. et al. Functional consequences of RNA 5\u2032-terminal deletions on coxsackievirus B3 RNA replication and ribonucleoprotein complex formation. J. Virol.91, e00423-e517 (2017).","journal-title":"J. Virol."},{"key":"67648_CR18","first-page":"882","volume":"3","author":"AV Gamarnik","year":"1997","unstructured":"Gamarnik, A. V. & Andino, R. Two functional complexes formed by KH domain containing proteins with the 5\u2019 noncoding region of poliovirus RNA. RNA3, 882\u2013892 (1997).","journal-title":"RNA"},{"key":"67648_CR19","doi-asserted-by":"publisher","first-page":"e01119-14","DOI":"10.1128\/mBio.01119-14","volume":"5","author":"B Holmblat","year":"2014","unstructured":"Holmblat, B. et al. Nonhomologous recombination between defective poliovirus and coxsackievirus genomes suggests a new model of genetic plasticity for picornaviruses. mBio5, e01119-14 (2014).","journal-title":"mBio"},{"key":"67648_CR20","doi-asserted-by":"publisher","first-page":"e1005266","DOI":"10.1371\/journal.ppat.1005266","volume":"11","author":"C Muslin","year":"2015","unstructured":"Muslin, C., Joffret, M.-L., Pelletier, I., Blondel, B. & Delpeyroux, F. Evolution and emergence of enteroviruses through intra- and inter-species recombination: plasticity and phenotypic impact of modular genetic exchanges in the 5\u2019 untranslated region. PLoS Pathog.11, e1005266 (2015).","journal-title":"PLoS Pathog"},{"key":"67648_CR21","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1038\/s41564-019-0465-y","volume":"4","author":"M Vignuzzi","year":"2019","unstructured":"Vignuzzi, M. & L\u00f3pez, C. B. Defective viral genomes are key drivers of the virus\u2013host interaction. Nat. Microbiol.4, 1075\u20131087 (2019).","journal-title":"Nat. Microbiol."},{"key":"67648_CR22","doi-asserted-by":"publisher","first-page":"e11275","DOI":"10.7554\/eLife.11275","volume":"5","author":"RY Sanchez David","year":"2016","unstructured":"Sanchez David, R. Y. et al. Comparative analysis of viral RNA signatures on different RIG-I-like receptors. Elife5, e11275 (2016).","journal-title":"Elife"},{"issue":"2636\u20132648","key":"67648_CR23","first-page":"2648a","volume":"34","author":"ALP Caforio","year":"2013","unstructured":"Caforio, A. L. P. et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur. Heart J.34(2636\u20132648), 2648a\u20132648d (2013).","journal-title":"Eur. Heart J."},{"key":"67648_CR24","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1093\/molbev\/msy096","volume":"35","author":"S Kumar","year":"2018","unstructured":"Kumar, S., Stecher, G., Li, M., Knyaz, C. & Tamura, K. MEGA X: molecular evolutionary genetics analysis across computing platforms. Mol. Biol. Evol.35, 1547\u20131549 (2018).","journal-title":"Mol. Biol. Evol."},{"key":"67648_CR25","doi-asserted-by":"publisher","first-page":"2698","DOI":"10.1128\/JCM.00542-06","volume":"44","author":"WA Nix","year":"2006","unstructured":"Nix, W. A., Oberste, M. S. & Pallansch, M. A. Sensitive, seminested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens. J. Clin. Microbiol.44, 2698\u20132704 (2006).","journal-title":"J. Clin. Microbiol."},{"key":"67648_CR26","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1093\/clinchem\/46.11.1851","volume":"46","author":"NJ Panaro","year":"2000","unstructured":"Panaro, N. J. et al. Evaluation of DNA fragment sizing and quantification by the agilent 2100 bioanalyzer. Clin. Chem.46, 1851\u20131853 (2000).","journal-title":"Clin. Chem."},{"key":"67648_CR27","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1128\/JCM.39.2.754-757.2001","volume":"39","author":"I Nachamkin","year":"2001","unstructured":"Nachamkin, I. et al. Agilent 2100 bioanalyzer for restriction fragment length polymorphism analysis of the Campylobacter jejuni flagellin gene. J. Clin. Microbiol.39, 754\u2013757 (2001).","journal-title":"J. Clin. Microbiol."},{"key":"67648_CR28","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/S0009-8981(01)00809-9","volume":"318","author":"C-Y Lu","year":"2002","unstructured":"Lu, C.-Y., Tso, D.-J., Yang, T., Jong, Y.-J. & Wei, Y.-H. Detection of DNA mutations associated with mitochondrial diseases by Agilent 2100 bioanalyzer. Clin. Chim. Acta 318, 97\u2013105 (2002).","journal-title":"Clin. Chim. Acta"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67648-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67648-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67648-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T14:25:16Z","timestamp":1670336716000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67648-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,20]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["67648"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-67648-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,20]]},"assertion":[{"value":"27 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11947"}}