Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Cytomegalovirus mediated myocarditis leads to cell death by parthanatos

A. Roth1, V. T. K. Le-Trilling2, M. Trilling2, J. Bernhagen3, U. Hendgen-Cotta4, T. Rassaf4, P. Lüdike4

1Cardio Science Labs, Universitätsklinikum Essen, Essen; 2Institut für Virologie, Universität Duisburg-Essen, Essen; 3Institut für Schlaganfall- und Demenzforschung, LMU Klinikum der Universität München, München; 4Klinik für Kardiologie und Angiologie, Universitätsklinikum Essen, Essen;

Background: Myocarditis is defined as an inflammation of the myocardium associated with cardiac dysfunction, often caused by viral infections. Cytomegalovirus (CMV) is a common cause of infection mainly in immunosuppressed patients and transplant recipients. The pathogenesis as well as the interaction between CMV infection, immune system response, genetic and environmental factors that lead to cardiac damage are yet unclear. Cell death via parthanatos, an inflammatory pathway characterized by caspase-independent activation of Poly (ADP‐ribose) Polymerase‐1 (PARP‐1) and translocation of Macrophage Migration Inhibitory Factor (MIF) into the nucleus, followed by DNA fragmentation has never been investigated in this context. We here aim to investigate if CMV infection leads to cell death by parthanatos in CMV infected hearts. Methods: Murine cardiomyocytes, endothelial cells, cardiac fibroblasts, and macrophages of WT and MIF KO hearts were isolated and infected with murine CMV (MCMV) in vitro and immunocompromised Signal Transducer and Activator of Transcription 2 (STAT2) KO mice, prone to viral infections, were infected with MCMV in vivo. Results: Using immunofluorescence staining, we identified hallmarks of parthanatos such as PARP-1 activation and nuclear MIF translocation. Since MIF is a key mediator of parthanatos, we also infected genetically depleted MIF knockout (KO) cells and could demonstrate significantly higher viability in these cells as well as reduced DNA fragmentation in comparison to wild type (WT) cells. Immunohistochemical staining of paraffin embedded tissue sections and light sheet analysis of hearts of STAT2 KO mice demonstrated cell damage by parthanatos at day 5 after MCMV infection. Conclusion: MCMV infection of murine cardiac cells leads to activation of parthanatos and subsequent cell death what can be attenuated by genetic deletion of MIF in vitro. Infection of immunocompromised STAT2 KO mice with MCMV likewise leads to induction of parthanatos in the murine heart in vivo. Whether this yet univestigated form of cell death accounts for the highly variable clinical course of myocarditis need to be addressed in translational studies.

https://dgk.org/kongress_programme/jt2022/aP873.html