The BK human polyomavirus (BKV) establishes a silent, persistent infection in the vast majority of healthy individuals. However, under conditions of immunosuppression (e.g., AIDS, BM transplantation, renal transplantation), high-level replication by BKV may ensue and result in a spectrum of severe urinary tract complications. In the setting of renal transplantation, BKV infection has emerged as a major cause of allograft dysfunction and failure. Due to the exquisite species specificity of Polyomaviridae, our understanding of the pathogenesis of BKV nephropathy (BKVN) following renal transplantation, as well as the development of effective therapies, is limited by the absence of a tractable animal model. To address this problem, we have developed an unique experimental model of polyomavirus infection in mice following kidney transplantation that mimics many of the important features of BKVN in clinical transplantation. The following key aspects of this model demonstrate why it is useful for studying BKV infection following transplantation: 1) mouse polyoma virus (PyV) is a ubiquitous and harmless pathogen wild mice, 2) acute PyV infection is rapidly cleared by immunocompetent hosts via a CD8+ T cell-dependent process, 3) following resolution of the acute infection, virus persists indefinitely in a number of tissues including the kidney but fails to cause pathology, and 4) acute PyV infection dramatically accelerates injury to allogeneic transplanted kidneys but not to syngeneic transplanted kidneys or native kidneys in transplanted mice. We will use the mouse PyV-kidney transplant model to address three specific aims. In the first aim we will evaluate the source and timing of PyV infection as well as the effects of clinically relevant immunosuppressive agents and anti-viral therapies on the development of PVAN. Studies of allograft function and survival will be complemented by analysis of the recipient anti-viral and anti-donor immune responses. In the second aim we will test the hypothesis that MHC matching, particularly at MHC class I loci, will result in improved recipient immunity to PyV and consequently reduced allograft injury. In addition, given the frequent use of fully HLA mismatched kidneys in clinical transplantation, we will test the hypothesis that innate immunity contributes to the control of PyV infection. In the third aim, we will determine the respective contributions of anti-viral and anti-donor T cell immunity to allograft injury in the setting of PyV infection. Specifically we will test the hypotheses that PVAN is mediated by 1) direct viral cytopathic effects, 2) an accentuated anti-donor T cell response induced by virally mediated inflammation, and/or 3) immunopathology mediated by PyV-specific T cells. The use of our mouse PyV-kidney transplant model will allow us to control many of the variables that have confounded our understanding of the pathogenesis of BKVN clinically. The results of these studies may directly lead to the development of new therapeutic approaches to prevent and treat BKV infection in human renal transplant recipients.
The human polyomavirus BK is increasingly recognized as a significant cause of dysfunction and failure of transplanted kidneys. Due to its tight species specificity BK virus can not be studied in animal models necessitating our development of a combined model of kidney transplantation and infection by the natural mouse polyoma virus. This mouse model will be used to define the mechanisms by which polyomavirus causes the failure of transplanted kidneys and to develop novel therapeutic interventions.
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