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

Award Number: K08HL157725
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/24/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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High-dimensional single-cell mapping to define immune signatures of cytomegalovirus-associated rejection in cardiac transplantation - 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 with the intellectual and technical training necessary to become an independent, R01-funded investigator with expertise in host-pathogen interactions and immune dysregulation in transplantation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $169,560 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	002	5	2/20/2025	NON-COMPETING CONTINUATION	$169,560
2025	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	3	1/30/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$87,355
2025	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	1/30/2025	NON-COMPETING CONTINUATION	-$87,355
														Subtotal = $169,560

Issue Date FY: 2024 ( Subtotal = $169,560 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	5/10/2024	NON-COMPETING CONTINUATION	$169,560
														Subtotal = $169,560

Issue Date FY: 2023 ( Subtotal = $244,620 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	002	3	9/11/2023	SUPPLEMENT FOR EXPANSION	$75,600
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	3	5/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$169,020
2023	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	5/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $244,620

Issue Date FY: 2022 ( Subtotal = $172,800 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	3/17/2022	NON-COMPETING CONTINUATION	$172,800
														Subtotal = $172,800

Issue Date FY: 2021 ( Subtotal = $172,440 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	3/10/2021	NEW	$172,440
														Subtotal = $172,440

Grand Total All Awards = $928,980

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

Award Number: K08HL157725

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/24/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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