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Human influenza a virus causes myocardial and cardiac-specific conduction system infections associated with early inflammation and premature death

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dc.affiliation.dptoUC3M. Departamento de Bioingenieríaes
dc.affiliation.grupoinvUC3M. Grupo de Investigación: Biomedical Imaging and Instrumentation Groupes
dc.contributor.authorFilgueiras Rama, David
dc.contributor.authorVasilijevic, Jasmina
dc.contributor.authorJalife, José
dc.contributor.authorNoujaim, Sami F.
dc.contributor.authorAlfonso, José M.
dc.contributor.authorNicolás Ávila, José A.
dc.contributor.authorGutiérrez, Celia
dc.contributor.authorZamarreño, Noelia
dc.contributor.authorHidalgo, Andrés
dc.contributor.authorBernabé, Alejandro
dc.contributor.authorCop, Christopher Pablo
dc.contributor.authorPonce Balbuena, Daniela
dc.contributor.authorGuerrero Serna, Guadalupe
dc.contributor.authorCalle, Daniel
dc.contributor.authorDesco Menéndez, Manuel
dc.contributor.authorRuiz Cabello, Jesús
dc.contributor.authorNieto, Amelia
dc.contributor.authorFalcón, Ana
dc.date.accessioned2021-10-07T11:09:55Z
dc.date.available2021-10-07T11:09:55Z
dc.date.issued2021-03-01
dc.description.abstractAims: Human influenza A virus (hIAV) infection is associated with important cardiovascular complications, although cardiac infection pathophysiology is poorly understood. We aimed to study the ability of hIAV of different pathogenicity to infect the mouse heart, and establish the relationship between the infective capacity and the associated in vivo, cellular and molecular alterations. //Methods and results: We evaluated lung and heart viral titres in mice infected with either one of several hIAV strains inoculated intranasally. 3D reconstructions of infected cardiac tissue were used to identify viral proteins inside mouse cardiomyocytes, Purkinje cells, and cardiac vessels. Viral replication was measured in mouse cultured cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to confirm infection and study underlying molecular alterations associated with the in vivo electrophysiological phenotype. Pathogenic and attenuated hIAV strains infected and replicated in cardiomyocytes, Purkinje cells, and hiPSC-CMs. The infection was also present in cardiac endothelial cells. Remarkably, lung viral titres did not statistically correlate with viral titres in the mouse heart. The highly pathogenic human recombinant virus PAmut showed faster replication, higher level of inflammatory cytokines in cardiac tissue and higher viral titres in cardiac HL-1 mouse cells and hiPSC-CMs compared with PB2mut-attenuated virus. Correspondingly, cardiac conduction alterations were especially pronounced in PAmut-infected mice, associated with high mortality rates, compared with PB2mut-infected animals. Consistently, connexin43 and NaV1.5 expression decreased acutely in hiPSC-CMs infected with PAmut virus. YEM1L protease also decreased more rapidly and to lower levels in PAmut-infected hiPSC-CMs compared with PB2mut-infected cells, consistent with mitochondrial dysfunction. Human IAV infection did not increase myocardial fibrosis at 4-day post-infection, although PAmut-infected mice showed an early increase in mRNAs expression of lysyl oxidase. //Conclusion: Human IAV can infect the heart and cardiac-specific conduction system, which may contribute to cardiac complications and premature deathen
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dc.identifier.bibliographicCitationFilgueiras-Rama, D., Vasilijevic, J., Jalife, J., Noujaim, S. F., Alfonso, J. M., Nicolas-Avila, J. A., Gutierrez, C., Zamarreño, N., Hidalgo, A., Bernabé, A., Cop, C. P., Ponce-Balbuena, D., Guerrero-Serna, G., Calle, D., Desco, M., Ruiz-Cabello, J., Nieto, A., & Falcon, A. (2020). Human influenza A virus causes myocardial and cardiac-specific conduction system infections associated with early inflammation and premature death. Cardiovascular Research, 117(3), 876–889.
dc.identifier.doihttps://doi.org/10.1093/cvr/cvaa117
dc.identifier.issn0008-6363
dc.identifier.publicationfirstpage876
dc.identifier.publicationissue3
dc.identifier.publicationlastpage889
dc.identifier.publicationtitleCARDIOVASCULAR RESEARCHen
dc.identifier.publicationvolume117
dc.identifier.urihttp://hdl.handle.net/10016/33386
dc.identifier.uxxiAR/0000028316
dc.language.isoeng
dc.publisherCambridge University Preesen
dc.rights© 2020 by the authors.en
dc.rightsAtribución 3.0 España
dc.rights.accessRightsopen accessen
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/
dc.subject.ecienciaBiología y Biomedicinaes
dc.subject.otherHeart Infectionen
dc.subject.otherHuman Influenza A Virusen
dc.subject.otherPremature Deathen
dc.subject.otherViral Replicationen
dc.titleHuman influenza a virus causes myocardial and cardiac-specific conduction system infections associated with early inflammation and premature deathen
dc.typeresearch article*
dc.type.hasVersionVoR*
dspace.entity.typePublication
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