Copper Deficiency Increases the Virulence of Coxsackievirus B3 Infections in Mice

Both selenium and vitamin E are important antioxidant nutrients. Previous studies have demonstrated that passage of coxsackievirus B3 (CVB3) through selenium or vitamin E deficient mice can rapidly select for more pathogenic variants. It has been proposed that oxidative stress may lead to enhanced rates of viral evolution. Copper deficiency is also associated with increased levels of oxidative stress. Thus, we were interested in determining if copper deficiency would lead to enhanced virulence and pathology in mice infected with CVB3. Pregnant Swiss outbred mice were fed a copper deficient diet and received 20 μg/ml copper, as copper sulfate, in the drinking water. On the day the dams gave birth, one half of the dams were switched to drinking water without added copper. Mice were weaned at 3 weeks of age and maintained on a deficient copper diet with or without added copper to the water. At 4–5 weeks of age, the mice were infected with 10 5 TCID 50 of coxsackievirus B3/20, a myocarditic strain, or B3/0, an amyocarditic strain. At seven days post‐infection, copper deficient mice infected with the B3/20 virus had significantly elevated heart and pancreatic titers compared to mice fed an adequate diet. Heart pathology also was increased in copper deficient mice infected with either the B3/20 or B3/0 strains of coxsackievirus. Additional studies are being conducted to determine if the enhanced virulence and pathology is due to alterations in the host immune response and/or to the appearance of more pathogenic viral strains in the copper deficient mice.