OVERALL: Mapping Immune Reponses to CMV in Renal Transplant Recipients SUMMARY/ABSTRACT Cytomegalovirus (CMV), a member of the Herpes virus family, has evolved alongside humans for thousands of years with a complex balance of latency, immune evasion, and transmission. While up to 70% of humans worldwide have evidence of CMV infection and seroprevalence approaches 100% in certain areas, healthy people show little to no clinical symptoms of primary infection. CMV disease is rarely observed in immune competent hosts because of innate immune responses and constant surveillance by natural killer (NK) and T cells that cooperatively control CMV. However, CMV is one of the most problematic pathogens in the immunocompromised host, after solid organ and stem cell transplantation causing increased risk of graft dysfunction, mortality and graft loss. We propose to study the innate and adaptive immune responses to CMV in immunocompromised solid organ transplant recipients using a high-throughput systems biology approach, carefully curated clinical phenotypes and novel statistical and computational approaches to: a) profile innate and adaptive immune responses during primary CMV infection and define the effects of CMV infection on the development of alloimmune responsiveness and transplant rejection; b) determine the role of NK cells in CMV reactivation and chronic transplant rejection and c) define the effects of CMV infection on the development of chronic allograft injury. The long-term goal of the proposed research is to develop a detailed molecular map of the cross-talk between the innate and adaptive immune response in primary and latent CMV infection in the transplant recipient. Detailed insights into the interaction of the virus with the immune system stand to generate concepts for more adequate vaccine strategies, risk assessment for CMV infection to better understand the immune system and to define the interplay of CMV infection and organ transplant injury.
OVERALL: Mapping Immune Reponses to CMV in Renal Transplant Recipients NARRATIVE Cytomegalovirus (CMV) is a ubiquitous, genetically stable herpes virus that infects approximately 70% of the human population and establishes lifelong persistence. Primary infections as well as latency normally occur asymptomatically in immunocompetent hosts. However, in immunocompromised persons, such as transplant recipients, coexistence of CMV with the host leads to viral reactivation and disease associated with high morbidity and mortality. Furthermore, chronic CMV infection accelerates senescence of the immune system with a resultant high level of chronic subclinical inflammation which drives transplant morbidity and loss. We will use high-throughput systems biology technologies and novel statistical and computational approaches to characterize the innate and adaptive immune response to CMV in the setting of solid organ transplantation. Understanding the components of the immune response to CMV will provide valuable insights into chronic rejection and identify new approaches to guide patient management and therapy.
