RT Journal Article
T1 Human influenza a virus causes myocardial and cardiac-specific conduction system infections associated with early inflammation and premature death
A1 Filgueiras Rama, David
A1 Vasilijevic, Jasmina
A1 Jalife, José
A1 Noujaim, Sami F.
A1 Alfonso, José M.
A1 Nicolás Ávila, José A.
A1 Gutiérrez, Celia
A1 Zamarreño, Noelia
A1 Hidalgo, Andrés
A1 Bernabé, Alejandro
A1 Cop, Christopher Pablo
A1 Ponce Balbuena, Daniela
A1 Guerrero Serna, Guadalupe
A1 Calle, Daniel
A1 Desco Menéndez, Manuel
A1 Ruiz Cabello, Jesús
A1 Nieto, Amelia
A1 Falcón, Ana
AB 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
PB Cambridge University Prees
SN 0008-6363
YR 2021
FD 2021-03-01
LK https://hdl.handle.net/10016/33386
UL https://hdl.handle.net/10016/33386
LA eng
DS e-Archivo
RD 30 abr. 2024