Widespread asymptomatic persistent polyomavirus BK infection can be activated in the course of severe immune impairment, an event, which may lead to urogenital disease in transplantation patients. After kidney transplantation, the polyomavirus associated nephropathy (PVAN) is a severe disorder that can result in loss of graft function. In contrast to other opportunistic infections, therapeutic approaches have no significant impact on the outcome of PVAN. So far, recovery is only observed after changes of immunosuppressive therapy patterns and restoration of immunological competence, which can be followed by downregulation of virus replication and resolution of disease in individual patients. These observations suggest that persistent BK virus (BKV) infection is tightly controlled by an intact immune system and thus remains at a subclinical level in the healthy individual. As a consequence, iatrogenic immunosuppression in renal transplantation has to be tuned very carefully. On one hand, it should be sufficient to avoid immune-mediated rejection of the graft but should also not be so effective that persistent virus infections can reactivate to a clinically significant level. Under these aspects, a discrete activation of immune system cells can be noticed after renal transplantation. This is signaled by inflammatory events, which are driven by cells contributing to the tissue-specific immune response. In this context, it is of note that BKV DNA is associated with peripheral blood cells (PBCs), which also take part in tissue rejection. Once involved in an immunological defense reaction, PBCs receive regulatory signals, which cause remarkable changes in their gene expression. Given that such a cell is a target of persistent BKV infection, it is reasonable to assume that the expression of viral genes is affected as well. So far, however, the type of the viral association with circulating blood cell populations is not unequivocally defined. To understand more precisely the influences of BKV in hematopoietic cells on the pathogenesis of BKV disease, the aim of this research application is the characterization of the state of BKV infection in circulating blood cells. Specifically, the type of intracellular association in different PBC subpopulations, the state of expression and activation in affected cells ex vivo, and the viral inducibility in vitro will be addressed. Answers to these questions will provide basic information on PBCs as targets of persistent BKV infection and their contribution to the virus load at sites of inflammation. The data will provide the platform for a better understanding of so far unknown cellular pathways of BKV regulation and their influence on disease progression. This will ultimately help to develop new strategies for prevention of disease and the evolution of new therapeutic strategies.
