Cytomegalovirus (CMV) continues to have a tremendous impact in transplant patients despite remarkable advances in its diagnosis, prevention and treatment. It can affect allograft function and increase patient morbidity and mortality through a number of direct and indirect effects. Patients may develop asymptomatic viremia, CMV syndrome or tissue-invasive disease. Emerging data suggests that immunologic monitoring may be useful in predicting the risk of late onset CMV disease. However, this herpesvirus is one of the most complex viruses to infect humans, and the intricacy of both innate and adaptive immune responses means that it has not yet been fully characterized. In this scenario while interferons (IFN) are universally acknowledged for their antiviral and immunostimulatory functions, there is increasing appreciation of the detrimental effects of inappropriate, excessive, or mistimed type I IFN responses in viral infections. Hence, this project will allow to determine the combined effect of organ or stem cell transplantation and immunosuppressive drugs on type I and III IFN response and whether IFN related immune function profiling/monitoring can be used to predict CMV infections and rejections. In particular, we plan to assess the incidence, timing and impact of CMV viremia in patients receiving solid organ or hematopoietic stem cell transplantation and to determine the level of viremia associated with adverse clinical outcomes. Moreover, the evaluation of IFN signature, of genetic variants in selected IFN-I/III pathways and the ability of PBMC, T cells and macrophages to up-regulate IFN-stimulated gene response after in vitro exposure to IFN will be performed before and after transplantation. A prediction model integrating virological, immunological, therapeutic and clinical data will be development and will be used to bring personalized medicine into clinical practice in the transplant population.
In the last decade, considerable progress has been made in our understanding of the immunobiology of CMV, and in the diagnosis and treatment of CMV disease, providing an excellent platform in the development of protective immune strategies. Nonetheless, CMV remains an unmet health problem of clinical relevance for a substantial portion of transplant patients. Indeed, CMV is considered an important infectious complication following solid organ and hematopoietic stem cell transplantation. CMV disease generally results from reactivation of latent infection originating from the recipient or donor. Future studies would need to focus on dissecting the innate immunity as well as the adaptive immune response to the whole viral antigenic repertoire, in order to acquire in-depth understanding of the immune mechanisms leading to the control of this persistent virus. Interestingly in SOT recipients on the same immune suppression, some will also develop severe infections or graft rejection, whereas others experience a good clinical outcome, indicating that the function of the immune system may contribute to the observed variation. Hence, additionally, investigations related to elucidating the innate immune correlate of protection are going to be essential to improve treatment and design novel immune therapeutics. Multiple studies have suggested that cytokines or specific cell populations may be biomarkers for solid organ transplantation outcome, but so far, no reliable marker has been identified. In this perspective, examination into immune evasion mechanisms needs to be augmented, since viral immune modulators could ultimately be exploited to combat CMV. In this scenario orchestrating when and how the innate immune system should respond to pathogenic microbes is a critical function during transplantation. Type I/III IFN response play a critical role in combating virus infection, mainly by inducing the expression of ISG that exert antiviral functions. Meanwhile, viruses including CMV have developed strategies to counteract IFNs. The inadequate IFN response may account for the progressive increase of CMV viral load in transplant patients, the disease progression and the ultimate fatal outcomes.
At the same time while IFNs-I are universally acknowledged for their antiviral and immunostimulatory functions, there is increasing appreciation of the detrimental effects of inappropriate, excessive, or mistimed type I IFN responses in viral infections. In this project we hypothesize that a dysregulation in the innate immune response would be associated with subsequent increased CMV infection risk whereas a well calibrated immune response could be protective from infection in transplant recipients. Therefore, we plan to perform a prospective observational study in large cohort of transplant recipients using serial measurements of IFN-I/III signature in the blood samples collected from patients before and after transplantation to determine its ability to predict CMV infection and disease outcome. In this regard, it has been shown that a primed IFN-I subnetwork can contribute to an immediate-early antiviral state induced by type II IFN activation of macrophages, with a potential further amplification loop contributed by transient induction of IFNbeta ( Kropp et al., J Virol 2011), supporting the importance to decipher the IFN-I/III signature in patients following solid organ and hematopoietic stem cell transplantation. Moreover, a limited number of studies have explored the role of IFNlmbda in regulation of herpesvirus infections and no studies have been performed evaluating IFNlambda1-3 expression in transplant patients who reactive CMV infection. This project aims also at investigating whether IFN-III signaling can be involved in CMV reactivation and whether SNPs in the IFNLambda 3 may have any effect on the ISGs expression as well as on incidence rate and outcome of active CMV infection in transplant patients. Lastly, we will also evaluate the ability of the transplant patients to mount an effective antiviral immune response after in vitro IFN stimulation. Indeed, higher responsiveness to IFN may restrict CMV replication to a greater extent, exerting better control on the adaptive immunity and leading to improved outcomes of CMV disease after transplantation. In this scenario, a prediction a model integrating virological, immunological (e.g. IFN signature, host genetics and in vitro IFN responsiveness), therapeutical and clinical data will be development, for the first time to our knowledge, to identify patients with the highest risk of CMV infections and rejections. This model will allow us to better describe many pathogenetic and clinical aspects observations in transplant patients of which several had long remained unexplained such as the understanding of the relationship between CMV reactivation, innate immune response and disease outcome in recipients in solid organ and hematopoietic stem cell transplantation.