IP-151 I I

SELENIUM AND ITS ROLE IN VIRAL PATHOGENESIS Melinda A. Beck, University of NC at Chapel Hill

Previous work in our laboratory has demonstrated that the selenium (Se) status of the host plays an important role in viral pathogenesis. Keshan disease, an endemic cardiomyopathy first described in China, was found to be associated with a deficiency in Se. In addition, an infectious co-factor, most likely a coxsackievirus, was also suggested based on the epidemiology of the disease. Animal models for Keshan disease developed in our laboratory demonstrated that a normally benign strain of coxsackievirus 83 could become virulent in a Se- deficient animal due to changes in the viral genome. Once these changes occur, even mice with normal Se status are now vulnerable to the pathogenic effects of the mutated virus. This was the first description of a deficiency in a specific nutrient inducing changes in a viral genome. To mimic the effect of a deficiency in Se, glutathione peroxidase I (GPX-I) knockout mice were also infected with the benign strain of coxsackievirus B3. Over 50% of the knockout mice developed myocarditis, which was found to be associated with a change in the viral genome. None of the wildtype mice developed any disease, and no changes in the viral sequence occurred. In Cuba, an epidemic of optic and peripheral neuropathy occurred in the early 199Os, which was associated with a decrease in antioxidant nutrient protection. A coxsackie-like virus was isolated from the cerebrospinal fluid from over 80% of individuals diagnosed with the disease. This virus was found to be very similar to coxsackievirus A9, although sequencing of the virus revealed mutations not found in any other known coxsackievirus. We hypothesize that a coxsackievirus A9 developed mutations when replicating in an oxidatively stressed host. Thus, Se is an important defense mechanism against oxidative stress in the host, not only for the host, but also for prevention of viral mutations.

(P-16/ ANTIOXIDANT FUNCTIONS OF METALLOTHIONEIN

Y. James Kang, Departments of Medicine, and Pharmacology & Toxicology, University of Louisville, Louisville, KY 40292

The antioxidant function of metallothionein (MT) was first suggested in the early 1980’s. Studies in vitro have revealed that MT directly reacts with ail reactive oxygen species of biological significance. However, demonstration of these reactions in intact animal studies has been extremely challenging. Nevertheless, both pharmacologic and genetic studies have shown that MT functions in protection against oxidative injury in vivo. In particular, the data gathered from our recent studies using a cardiac-specific, MT- overexpressing transgenic mouse model have provided direct evidence to support this physiological role of MT. Under acute and chronic oxidative stress conditions such as treatment with doxorubicin, ischemia-reperfusion and dietary copper restriction, MT-overexpressing transgenic mouse hearts displayed a marked resistance to the injurious consequences, including biochemical, pathological and functional alterations. This protective action of MT correlates with its inhibition of reactive oxygen species- induced lipid peroxidation and mitogen-activated protein kinases- mediated apoptosis. A critical elucidation of the mechanism of action of MT as an antioxidant in viva remains to be achieved. However, the combination of recent understanding of the metal thiolate cluster structure of MT and molecular genetic approaches has provided the basis of further advancement in this field.

OXYGEN ’ 9 9 s9