Transplanting encephalomyocarditis virus-infected porcine islet cells reverses diabetes in recipient mice but also transmits the virus.

Abstract

Previous studies demonstrated that porcine encephalomyocarditis virus (EMCV) caused acute and persistent infection in the myocardium, central nervous system, and spleen of non-human primates (cynomolgus macaques); and it productively infected primary human cardiomyocytes, suggesting that the virus may pose a risk in pig-to-human transplantation. Recently, transplantation of myocardial and pancreatic tissues from acutely infected pigs transmitted the virus to recipient mice, resulting in acute fatal EMCV disease. Here, we examined whether porcine islet cells (PICs), which are under clinical trial for treatment of type I diabetes in humans, are susceptible to porcine EMCV, and whether EMCV-infected PICs could function in vivo to reverse diabetes. PICs were infected with EMCV in vitro for 5 h, and resulting insulin production compared with that produced by uninfected PICs. Subsequently, infected PICs were transplanted intra-abdominally or under the kidney capsule of C57BL/6 mice, and both virus transmission and PIC function analyzed. PICs were highly susceptible to porcine EMCV, resulting in a 1500-fold increase in production of infectious virus within 5 h of inoculation and cytolysis that destroyed up to 50% of cells within 96 h. However, as long as they were viable, infected PICs produced insulin at levels comparable with uninfected PICs. Intra-abdominal transplantation of 2000 PICs, infected with one plaque forming unit (pfu) per cell of porcine EMCV, into C57BL/6 mice transmitted the virus resulting in acute fatal EMCV disease characterized by hind limb paresis and paralysis and acute respiratory distress in 40% of recipient mice. More importantly, transplantation of 2500 EMCV-infected PICs under the kidney capsule of diabetic C57BL/6 mice (glucose level > or =350 mg/dl) reversed diabetes in 83% of recipient mice (glucose level < or =170 mg/dl); however these mice succumbed to acute EMCV disease transmitted by the xenograft 5 days after transplantation. EMCV infection does not appear to affect insulin production by PICs, but infected xenografts can transmit the virus to recipient animals, resulting in severe disease.