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

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $169,560

## Abstract

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 200 heart transplant recipients at the Massachusetts General Hospital (MGH)
Transplant Center. 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 Center for Immunology and Inflammatory diseases (CIID) at MGH under the mentorship of
Dr. Andrew Luster and Dr. Alexandra-Chloe Villani. The CIID is a state-of-the-art multidisciplinary research
center focused on mechanisms of immune-mediated inflammatory diseases and is the foundation for
immunology research at MGH. Dr. Sen has devised a career development plan consisting of coursework and
hands-on training in single-cell ‘omics,’ bioinformatics, the biology of alloimmunity and tolerance, cardiac tissue
microenvironments, in vivo host-pathogen interactions, and human subjects research, as well as organized a
Training Advisory Committee, chaired by Dr. Joren Madsen, to provide expertise and assistance in these areas.
The K08 award will provide Dr. Sen wi...

## Key facts

- **NIH application ID:** 10838579
- **Project number:** 5K08HL157725-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Pritha Sen
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $169,560
- **Award type:** 5
- **Project period:** 2023-04-24 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838579

## Citation

> US National Institutes of Health, RePORTER application 10838579, High-dimensional single-cell mapping to define immune signatures of cytomegalovirus-associated rejection in cardiac transplantation (5K08HL157725-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10838579. Licensed CC0.

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