Mechanisms of interaction between the influenza virus and the infected cell



Amelia Nieto

Group Leader



Research summary

Influenza virus employs an unusual RNA transcription mechanism that uses as primers short-capped oligonucleotides scavenged from newly synthesized RNA polymerase II transcripts; thus influenza virus stablishes a network of virus-host functional interactions which depends on chromatin dynamic and therefore on epigenetic modifications. We study the epigenetic changes elicited by influenza virus and also identify pathogenicity factors present in circulating viruses and their contribution with cardiovascular complications.



Filgueiras-Rama D, Vasilijevic J, Jalife J, Noujaim SN, Alfonso JM, Nicolas-Avila JA, Gutierrez C, Zamarreño N, Hidalgo A, Bernabé A, Cop CP, Ponce-Balbuena D, Guerrero-Serna G, Calle D, Desco M, Ruiz-Cabello J, Nieto A, Falcon A.Human Influenza A virus causes myocardial and cardiac-specific conduction system infection associated with early inflammation and premature death. Cardiovasc Res 2020 Apr 28:cvaa117. doi: 10.1093/cvr/cvaa117.

Marcos-Villar L, Nistal-Villan E, Zamarreño N, Garaigorta U, Gastaminza P, Nieto A. Interferon- Stimulation Elicited by the Influenza Virus Is Regulated by the Histone Methylase Dot1L through the RIG-I-TRIM25 Signaling Axis.. Cells. 2020 Mar 16;9(3):732. doi: 10.3390/cells9030732.

Marcos-Villar L, Nieto A The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy. Sci Rep 2019 Nov 14;9(1):16862. doi: 10.1038/s41598-019-53239-6. PMID: 31727944 8

Nieto, A., Vasilijevic, J., Brito-Santos, N., Zamarreño, N. López, P., Amorim, M.J., Falcón, A. Mutation S110L of H1N1 Influenza Virus Hemagglutinin: A Potent Determinant of Attenuation in the Mouse Model. . Front. Immunology. 06 February 2019 |

Pazo, A., Pérez-González, A., Oliveros, J.C., Huarte, M., Chavez, J. P., Nieto, A. hCLE/RTRAF-HSPC117-DDX1-FAM98B: A New Cap-Binding Complex That Activates mRNA Translation. Front Physiol 2019 Feb 18;10:92. doi: 10.3389/fphys.2019.00092. eCollection 2019


Influenza A virus (IAV) promotes epigenetic modification in the infected cells. IAV infection increases the methylation of lysine 79 of histone 3 catalyzed by Dot1L enzyme. A decreased antiviral signaling mediated by RIG-I sensor is found in Dot1L-inhibited cells, infected with IAV. Accordingly, Dot1L inhibition decreases the IFN-β promoter stimulation and RIG-I-MAVS association upon viral infection. Interferon-inducible protein TRIM25 expression increases in influenza virus infected cells, but Dot1L inhibition reduces both the TRIM25 expression and TRIM25 protein levels. TRIM25 overexpression reverses the defective innate response mediated by Dot1L inhibition elicited upon virus infection or by overexpression of RIG-I signaling intermediates. Thus, TRIM25 is a control point of the RIG-I recognition pathway controlled by Dot1L and may have a general role in RNA viruses recognized by the RIG-I sensor.


Human influenza A virus (hIAV) infection is associated with important cardiovascular complications, although cardiac infection pathophysiology is poorly understood. We evaluated lung and heart viral titers in mice infected with either one of several hIAV strains inoculated intranasally and identified viral replication inside mouse cardiomyocytes, Purkinje cells, and cardiac vessels. In addition, we used human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) to confirm cardiac infection and studied the underlying molecular alterations associated with the in vivo electrophysiological phenotype. Both, pathogenic and attenuated hIAV strains infected and replicated in cardiomyocytes, Purkinje cells, hiPSC-CMs and cardiac endothelial cells. Cardiac conduction alterations and high mortality rates were especially pronounced in mice infected with the highly pathogenic strain, compared with mice infected with the attenuated strain. Thus, human IAV can infect the heart and cardiac specific conduction system, which may contribute to cardiac complications and premature death.






Amelia Nieto Principal investigator
Ana Falcón Postdoctoral scientists
Laura Marcos-Villar Postdoctoral scientists
Noelia Zamarreño Technician

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