Pathogenesis of coxsackievirus-B5 acquired from intra-renal porcine islet cell xenografts in diabetic mice

Background: We previously demonstrated the ability of a human isolate of coxsackievirus-B5 (CVB5) to infect productively adult porcine islet cells (PICs) in vitro. PICs infected with CVB5 remain viable, and upon transplantation reversed diabetes in C56BL/6 mice for up to 5 days. Methods: In the present work, we expanded this graft-to-host xenozoonosis model by examining the long-term functionality of CVB5-infected PIC xenografts in immunosuppressed mice. And, we characterized the pathogenesis of CVB5 infection in mice resulting from directional transmission of the virus from PIC xenografts to surrounding tissues in a mouse model for immunosuppressed human PIC xenograft recipients. Results: Both acutely (12 h) and chronically (72 h) infected PIC xenografts functioned in vivo to reverse diabetes in mice. The efficacy of both infected and un-infected PICs was transient beyond 5 days post-inoculation and the long-term functionality of the grafts was compromised by host-to-graft rejection. CVB5-infected PIC xenografts transmitted infectious virus to immunosuppressed recipient mice resulting in extensive histopathologic changes. The virus replicated in the heart, liver, spleen, kidney, pancreas, brain and skeletal muscle in higher levels in severe-combined immunodeficient (SCID) mice that were directly inoculated with virus when compared to controls. In addition, infectious virus was recovered for up to 22 days after inoculation in SCID mice whereas it was only detected up to Day 4 PI in non-SCID mice. Conclusions: Immunosuppressed PIC xenograft recipients may be more susceptible to infection with CVB5 which could target the xenograft leading to disseminated infection in the host.