High-dimensional single-cell mapping to define immune signatures of cytomegalovirus-associated rejection in cardiac transplantation

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PROJECT SUMMARY Human cytomegalovirus (CMV) is the most common viral infection to complicate cardiac transplantation and is an important risk factor for cellular rejection. While CMV causes damage to native organs through direct viral cytopathic effect, CMV-mediated cardiac allograft rejection is attributed to “immune dysregulation,” the mechanisms for which are not well understood. This information is critical to the field of transplantation, as treatment of cellular rejection, even in cases with concurrent CMV viremia, includes immunosuppression, an approach that confers risk of abrogation of viremic control and precipitation of CMV-related morbidity, including worsening rejection and other opportunistic infections. While cellular rejection is mediated by cytotoxic T lymphocytes (CTL), recent paradigm-shifting work has demonstrated that activated mononuclear-phagocytic (MP) cells also have a critical role in driving allograft rejection through trained immunity. These findings are intriguing in the context of CMV-mediated graft rejection as MP cells are an important CMV viral reservoir. The central hypothesis being tested in this proposal is that CMV-mediated dysregulation of the MP system triggers a unique rejection phenotype that drives the infiltration of distinctly proliferative and alloreactive CTL into cardiac allograft tissue. The objective of this proposal is to leverage multi-omics strategies, including scRNA-seq and CITE-seq, to decode the allograft tissue microenvironment in rejection during CMV viremia, with a focus on understanding how MP cells orchestrate alloreactive CTL responses (Aim 1) and determine if tissue MP and CTL cell states are reflected in the blood (Aim 2). To accomplish this, we will study endomyocardial tissue and paired blood from a cohort of 220 heart transplant recipients at MassGeneralBrigham (MGB). These studies will distinguish CMV-mediated and CMV-independent mechanisms of cellular rejection, allowing for the development of diagnostic tools and rejection treatment strategies tailored to viral or non-viral causes, promoting precision medicine in cardiac transplantation. Dr. Sen will perform the work in this K08 proposal in the Transplant and Oncology Infectious Diseases Group at Brigham and Women’s Hospital (BWH), with continued affiliation with the Center for Immunology and Inflammatory diseases at Massachusetts General Hospital (MGH), Cell Circuits Group at the Broad Institute (MIT) and Harvard Medical School (HMS). Dr. Sen has devised a career development plan consisting of coursework, hands-on training, and expert mentorship in single-cell ‘omics,’ bioinformatics, the biology of alloimmunity and tolerance, cardiac tissue microenvironments, in vivo host- pathogen interactions, and human subjects research. The K08 award will provide Dr. Sen with the training necessary to become an independent, R01-funded investigator with expertise in host-pathogen interactions and immune dysregulation in transplantation.