Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence
| Autor: | Ryan P. Gilley, Yanbao Yu, David M. Brown, Peter H. Dube, Norberto Gonzalez-Juarbe, Maryann P. Platt, Yi-Han Lin |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Programmed cell death Heart Diseases Proteome Physiology media_common.quotation_subject Necroptosis 030204 cardiovascular system & hematology Mitochondrion Proteomics Bioinformatics medicine.disease_cause Article Cell Line Mice 03 medical and health sciences 0302 clinical medicine Orthomyxoviridae Infections medicine Animals Humans Myocytes Cardiac media_common business.industry Convalescence Phosphoproteomics Phosphoproteins Rats Mice Inbred C57BL Oxidative Stress 030104 developmental biology Influenza A virus Cardiology and Cardiovascular Medicine business Protein Kinases Oxidative stress |
| Zdroj: | Circ Res |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.120.318511 |
| Popis: | Rationale: Patients with and without cardiovascular diseases have been shown to be at risk of influenza-mediated cardiac complications. Recent clinical reports support the notion of a direct link between laboratory-confirmed influenza virus infections and adverse cardiac events. Objective: Define the molecular mechanisms underlying influenza virus–induced cardiac pathogenesis after resolution of pulmonary infection and the role of necroptosis in this process. Methods and Results: Hearts from wild-type and necroptosis-deficient (MLKL [mixed lineage kinase domain-like protein]-KO) mice were dissected 12 days after initial influenza A virus (IAV) infection when viral titers were undetectable in the lungs. Immunofluorescence microscopy and plaque assays showed presence of viable IAV particles in the myocardium without generation of interferon responses. Global proteome and phosphoproteome analyses using high-resolution accurate mass-based LC-MS/MS and label-free quantitation showed that the global proteome as well as the phosphoproteome profiles were significantly altered in IAV-infected mouse hearts in a strain-independent manner. Necroptosis-deficient mice had increased survival and reduced weight loss post-IAV infection, as well as increased antioxidant and mitochondrial function, indicating partial protection to IAV infection. These findings were confirmed in vitro by pretreatment of human and rat myocytes with antioxidants or necroptosis inhibitors, which blunted oxidative stress and mitochondrial damage after IAV infection. Conclusions: This study provides the first evidence that the cardiac proteome and phosphoproteome are significantly altered post–pulmonary influenza infection. Moreover, viral particles can persist in the heart after lung clearance, altering mitochondrial function and promoting cell death without active replication and interferon responses. Finally, our findings show inhibition of necroptosis or prevention of mitochondrial damage as possible therapeutic interventions to reduce cardiac damage during influenza infections. Graphic Abstract: A graphic abstract is available for this article. |
| Databáze: | OpenAIRE |
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