Investigation of the translational potential of the ISG15 system for treatment of virus-induced inflammatory cardiomyopathy.

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Myocarditis is a condition resulting from inflammation of the heart muscle, which in developed countries most commonly results from a viral infection. The course of viral myocarditis is most severe in childhood, with up to 55% mortality in infants. In about 20% of affected patients, acute viral infection triggers chronic inflammatory disease of the heart resulting in cardiac dysfunction with 35% five-year mortality rates. The paramount clinical impact of myocarditis is in contrary to a substantial lack of therapeutic strategies, which target the pathogen and simultaneously manipulate the immune response for the benefit of the host. It has been demonstrated for different pathogens that it is feasible to take advantage of endogenous innate immune effector systems to extend the antiviral therapeutic repertoire. We have recently identified a potent cardiomyocyte-intrinsic defense pathway that acts downstream of such innate responses, which is the Interferon-stimulated gene of 15 kDa (ISG15) protein modification system. ISG15 counteracts viral pathology and preserves immune homeostasis during viral myocarditis, thereby preventing cardiac remodeling, persistence of viral genomes and chronic inflammation. Conjugation of proteins with ISG15 in the heart in particular is needed for preserving survival. In this proposal, we aim to investigate the translational potential of ISG15/ISGylation in a cell-specific manner for heart tissue. The main goal is to target different molecules within the ISG15 protein modification cascade to enhance ISGylation. Therefore, we will implement Adeno-associated virus-induced vector technology and novel in vivo model systems that will eventually enable increased ISG15 expression, stabilization of ISGylated proteins and/or lead to hyper-ISGylation of proteins in heart tissue. Identification of the molecular mechanisms, by which ISG15 limits expansion of viral pathogens in the heart and alleviates detrimental immune responses, will involve ISG15 substrate identification studies by mass spectrometry. The findings of these experiments will guide proof-of-concept experiments that aim for improving disease progression of myocarditis and inflammatory cardiomyopathy in humans. Thereby, both the biochemical analysis of human ISG15 and the application of pluripotent stem cell technology represent critical steps towards the development of suitable therapeutic approaches for high-risk patients in the future.