Background: Coxsackievirus type B3 (CVB3) is a cardiotropic enterovirus. Infection causes cardiomyocyte necrosis and myocardial inflammation. The damaged tissue that results is replaced with fibrotic or calcified tissue, which can lead to permanently altered cardiac function. The extent of pathogenesis among individuals exposed to CVB3 is dictated by a combination of host genetics, viral virulence, and the environment. Here, we aimed to identify novel, therapeutically targetable CVB3 susceptibility genes.

Methods and Results: 129S1 mice infected with CVB3 developed increased cardiac pathology compared to 129X1 substrain mice despite no difference in viral burden. Linkage analysis identified a major locus on chromosome 7 (LOD: 8.307, P<0.0001) that controlled the severity of cardiac calcification and necrosis following infection. Sub-phenotyping and genetic complementation assays identified Abcc6 as the underlying gene. Microarray expression profiling identified genotype-dependent regulation of genes associated with mitochondria. Electron microscopy examination showed elevated deposition of calcium crystals (hydroxyapatite) in matrices of mitochondria from infected Abcc6-deficient (Abcc6-/-) mice. Cardiac necrosis and calcification in Abcc6-/- mice was reduced by more than half by treatment with cyclosporine A (CsA) but not by FK506, an immunosuppressant drug similar to CsA that does not target the mitochondrial transition pore (mPTP) regulator, CypD. Furthermore, CsA had no effect in the CVB3-induced phenotype of doubly deficient CypD-/-Abcc6-/- mice.

Conclusions: Mutations in Abcc6 render mice more susceptible to cardiac calcification following CVB3 infection. Pharmacological targeting implicates CypD in the control of cardiac necrosis and calcification in Abcc6-deficient mice, whereby CypD inhibition is required for cardioprotection.