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Projekt
Functional characterization of ubiquitin-like modifier ISG15 in murine enterovirus myocarditis
Antragstellerin
Professorin Dr. Antje Beling
Fachliche Zuordnung
Zellbiologie
Förderung
Förderung von 2011 bis 2015
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 197394206
Acute viral myocarditis may result in chronic virus persistence and ongoing disease eventually leading to heart failure with severe complications and high mortality particularly in young people. Within the acute infectious state the myocardium undergoes fundamental changes: post-translational modifications of proteins by the ubiquitin-like protein (Ubls) ISG15 seem to be an important regulatory principle in the adaptation of cells in viral disease. Within the context of ongoing murine Coxsackievirus B3 (CVB3)- myocarditis the cardiac expression of both ISG15 and ISGylating enzymes, and thus ISGylation were found to be delayed in mice being susceptible to ongoing disease. CVB3 myocarditis has been investigated in ISG15-/- mice revealing severe myocarditis, increased viral load, ongoing chronic disease with virus persistence resulting in high grade myocardial fibrosis, and enhanced mortality. To discriminate the contribution of protein modification with ISG15 from putative cytokine effects of secreted ISG15, CVB3-myocarditis shall be studied in mice with distinct ISGylation-enzyme defects: UBE1L-/--mice and transgenic UBP43-mice with silenced enzyme activity will be studied. In an attempt to identify mechanisms of antiviral action of ISG15, research will aim on the identification of ISG15 targets that are known to interfere with CVB3 replication as well as of ISGylated protein substrates within the CVB3 polyprotein. The role of ISG15 in adaptive immunity in CVB3-infection will be followed by lymphocyte transfer studies of CD4+ T cell, B cells as well as of memory CD8+ T cells.
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