Lay summary
Transplantation of solid organs or cells can be lifesaving. Unfortunately, due to the current organ shortage, not all potential recipients can profit from this option. Xenotransplantation, i.e. transplantation across the species barrier, might be an alternative approach. Recent progress in overcoming immunological barriers using genetically engineered pigs has been very promising. Besides immunological and physiological barriers, the potential for xenogeneic infections has been a major concern. Much emphasis has been devoted to donor-derived infections, while infection of the graft by recipient pathogens has only recently been appreciated.
In transplantation medicine, infections represent a major cause of morbidity and mortality. Infections not only cause direct damage but there is also increasing evidence for indirect effects such as vasculopathy and graft rejection. Human cytomegalovirus (CMV) is one of the most important pathogens posttransplant. Whereas it establishes life-long latent infection in immunocompetent hosts, it frequently reactivates in immunosuppressed transplant recipients and potentially triggers graft rejection. Similar to the human experience, porcine CMV was found to cause tissue damage in preclinical pig-to-baboon xenotransplantation, and induced a consumptive coagulopathy in the recipient animal.
The endothelium maintains an anti-inflammatory and anti-coagulant environment under physiological conditions. Forming the interface between the graft and the recipient, several mechanisms including CMV infection target the endothelium and disrupt this delicate balance. CMV infection can contribute to the recruitment of host leukocytes and the activation of cellular immune responses. Beside immunosuppressive therapy, the intrinsic ability of the graft endothelium to resist the potential injuries mediated by ischemia/reperfusion, CMV infection, and the consequent immune responses is absolutely crucial for ultimately maintaining graft function.
The immediate goal of the present proposal is to elucidate the molecular effects of CMV infection in endothelial cells and to develop strategies to prevent graft injury mediated by pro-inflammatory and pro-coagulant responses to CMV infection. Using several genetically engineered endothelial cell lines in an established in vitro model we will dissect the molecular mechanisms of cross-species CMV infection using the allogeneic system as control. The following specific aims will be addressed:
Aim #1:Analyze interactions of human leukocytes with CMV-infectedendothelial cells
Aim #2: Examine pro-coagulant changes in CMV-infected endothelialcells
Aim #3: Investigate inhibition of innate inflammatory responses by SOCS 1and 3 in CMV-infected endothelial cells
The outlined experiments will improve our understanding of the CMV-induced mechanisms resulting in EC alterations, particularly human CMV infection in porcine EC, and will provide evidence for the potential of different interventional approaches. This knowledge may then help us to design better prophylactic or preemptive therapies in both the human allotransplantation setting, and in xenotransplantation. If xenotransplantation proceeds to the clinical stage, the potential role of cross-species CMV infection will be crucial to guide clinical trials