Editors' ChoiceCongestive Heart Failure

The Ubiquitinase Pathway Takes Center Stage in Viral Myocarditis

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Science Translational Medicine  10 Sep 2014:
Vol. 6, Issue 253, pp. 253ec155
DOI: 10.1126/scitranslmed.3010402

Almost every practicing cardiologist has at one time faced a young, healthy patient and had to explain that their heart is failing because of viral myocarditis. The answer to the inevitable “Why?” lies in the interplay of immune response, viral infection, and cardiac physiology, but details have remained elusive. Rahnefeld et al. have taken a substantial step toward a better understanding of inflammatory cardiomyopathy by studying the innate immune system and its response to Cocksackie virus (CVB3) infection in the heart.

The authors studied a mouse that lacked the Interferon Stimulated Gene-15 (ISG15), a small protein composed of two ubiquitin folds and known to be a substrate of the E1-E2-E3 ubiquitinase signaling system. Mice lacking either ISG15 or the genes required to conjugate it to a target protein had both increased mortality and worsened congestive heart failure compared with control mice infected with CVB3. Because ISG15 and the ubiquitinase system target proteins for degradation, Rahnefeld et al. hypothesized that ISG15 may directly target a viral protein and thus limit infection-related pathology.

CVB3 uses its own protease to shut down the translational machinery of the host and make room for its own viral replication. ISG15 was found to interact with CVB-protease 2A (2APro), and followup studies showed that 2APro activity was inhibited by ISG15. Likewise, viral replication studies in human cardiomyocytes showed decreased viral replication, and a small patient study showed that ISG15 was indeed up-regulated in cardiac biopsies of patients with viral myocarditis.

It’s no mystery that mice are different than people, and even bigger differences can be seen in mechanisms of immunity. But with this and more studies of its kind, we may one day be able to give myocarditis patients more than a shrug of the shoulder. Instead, we look forward to mechanistically centered treatments to prevent heart failure.

A. Rahnefeld et al., Ubiquitin-like protein ISG15 in host defense against heart failure in a mouse model of virus-induced cardiomyopathy. Circulation 10.1161/CIRCULATIONAHA.114.009847 (2014). [Abstract]

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