Heritable biochemical idiosyncrasies are thought to help explain the variable outcome when individuals in the outbred human population are exposed to pathogens. However, even in relatively tractable mouse models, there are surprisingly few clear examples of biochemical differences that can account for the characteristic sensitivity of some inbred strains to specific viruses. The coxsackievirus studied here by Opavsky et al. can infect lymphocytes and macrophages, as well as myocytes and other cell types in many organs. In some humans and in particular strains of mice, infection of the heart provokes dilated cardiomyopathy and can lead to heart failure. Earlier work showed that the MAP kinase signaling is induced by infection and suggested that this pathway might contribute to efficient viral replication. The authors have now identified signaling molecules essential for viral infection in vitro, including the kinase p56Lck, which mediates signals from the T cell receptor, and the Erk kinases, which act downstream of p56Lck in T cells and activate the MAP kinase pathway in many cell types. Drugs and genetic lesions that block this signaling pathway prevent viral replication in cultured cardiomyocytes and T cell lines. Opavsky et al. show here that viral infection correlates with ERK activation in vivo as well, since a mouse strain that is insensitive to the cardiac disease shows markedly reduced ERK activation following exposure to the virus relative to another, sensitive strain. The genetic differences underlying the distinct biochemical phenotypes of these strains remain to be discovered.

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Contact: John Ashkenas
scied@the-jci.org
416-946-7593
Journal of Clinical Investigation
12-Jun-2002

Page: 1
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