The role of transgenic knockout models in defining the pathogenesis of viral heart disease.

The pathogenesis of viral myocarditis involves contributions from the virus, the immune system and myocytes. In defining the molecular contributions in the disease process, modulations of the components of the immune system through transgenic knockout models provide useful insights. Advantages of the transgenic knockout models are that they allow biological evaluation of the importance of a particular molecule in the physiological context of an intact organism. Furthermore, the techniques of transgenic knockout models are now standardized, even though they are still technically challenging and time consuming. An example in myocarditis is the IRF-1 knockout mouse, where there is a complete absence of the inducible form of nitric oxide synthetase in the tissues. These animals are exquisitely sensitive to coxsackieviral infection, with extremely high mortality. On the other hand, CD4 knockouts appear to still have myocarditis in an autoimmune myocarditis model, while p56lck knockouts (the T-cell tyrosine kinase signalling molecule) appears to be free of viral myocarditis. These elegant systems of molecular manipu-lation should allow us unique insights into the pathogenesis of myocarditis.