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

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dc.contributor.author Filgueiras Rama, David
dc.contributor.author Vasilijevic, Jasmina
dc.contributor.author Jalife, José
dc.contributor.author Noujaim, Sami F.
dc.contributor.author Alfonso, José M.
dc.contributor.author Nicolás Ávila, José A.
dc.contributor.author Gutiérrez, Celia
dc.contributor.author Zamarreño, Noelia
dc.contributor.author Hidalgo, Andrés
dc.contributor.author Bernabé, Alejandro
dc.contributor.author Cop, Christopher Pablo
dc.contributor.author Ponce Balbuena, Daniela
dc.contributor.author Guerrero Serna, Guadalupe
dc.contributor.author Calle, Daniel
dc.contributor.author Desco Menéndez, Manuel
dc.contributor.author Ruiz Cabello, Jesús
dc.contributor.author Nieto, Amelia
dc.contributor.author Falcón, Ana
dc.date.accessioned 2021-10-07T11:09:55Z
dc.date.available 2021-10-07T11:09:55Z
dc.date.issued 2021-03-01
dc.identifier.bibliographicCitation Filgueiras-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.issn 0008-6363
dc.identifier.uri http://hdl.handle.net/10016/33386
dc.description.abstract Aims: 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 death
dc.format.extent 14
dc.language.iso eng
dc.publisher Cambridge University Prees
dc.rights © 2020 by the authors.
dc.rights Atribución 3.0 España
dc.rights.uri http://creativecommons.org/licenses/by/3.0/es/
dc.subject.other Heart Infection
dc.subject.other Human Influenza A Virus
dc.subject.other Premature Death
dc.subject.other Viral Replication
dc.title Human influenza a virus causes myocardial and cardiac-specific conduction system infections associated with early inflammation and premature death
dc.type research article
dc.subject.eciencia Biología y Biomedicina
dc.identifier.doi https://doi.org/10.1093/cvr/cvaa117
dc.rights.accessRights open access
dc.identifier.publicationfirstpage 876
dc.identifier.publicationissue 3
dc.identifier.publicationlastpage 889
dc.identifier.publicationtitle CARDIOVASCULAR RESEARCH
dc.identifier.publicationvolume 117
dc.identifier.uxxi AR/0000028316
dc.affiliation.dpto UC3M. Departamento de Bioingeniería
dc.affiliation.grupoinv UC3M. Grupo de Investigación: Biomedical Imaging and Instrumentation Group
dc.type.hasVersion VoR
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