Monday, June 30, 2025 6/30/2025

A critical role for macrophage ferroptosis in promoting fungal invasion in lung transplant recipients

Award Number: R01HL157414
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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A critical role for macrophage ferroptosis in promoting fungal invasion in lung transplant recipients - PROJECT SUMMARY/ ABSTRACT This application focuses on the contribution of transplant hemorrhage-induced iron overload in the dysregulation of pulmonary macrophages (mɸs) and the promotion of invasive aspergillosis. Aspergillus fumigatus (Af) is a ubiquitous mold that releases airborne spores (conidia) and affects nearly 20 million people worldwide. One-in- three lung transplant recipients (LTRs) suffers from Aspergillus-related pulmonary disease. While lung transplantation can be a life-saving treatment for thousands of people, survival post-transplant is often limited by Af infection. To better understand the transplant (host)-Af (pathogen) relationship, we developed a murine orthotopic tracheal transplant (OTT) model of Af infection. We have shown that transplant rejection-mediated microhemorrhage increases tissue iron levels and determines Af invasion. However, the exact interaction between immunity, iron overload and infection are still poorly understood. Mɸs are the first line of defense against Af and are also central to restoring tissue iron homeostasis. Importantly, our preliminary results indicate that microhemorrhage-mediated iron overload: (i) profoundly impacts the ability of mfs to kill Af conidia through a defect in lysosomal acidification; (ii) the innate immune response is polarized toward a pro-inflammatory mɸs state that results in high levels of tissue damaging reactive oxygen species (ROS); and (iii) iron promotes mɸ ferroptosis. Ferroptosis is a newly recognized form of regulated cell death that results from the production of iron toxic lipid ROS. Ferroptosis was first recognized in cancer but is now known to contribute to Alzheimer’s and Parkinson’s disease, ischemia reperfusion injury, atherosclerosis, acute kidney injury and the response to acute hemorrhage. However, the role of ferroptosis in lowering the host’s defense against pathogens, if any, remains unknown. The proposed studies are designed to address these questions in terms of Af invasion. The central hypothesis is that transplant microhemorrhage-mediated iron overload induces mf ferroptosis and polarization into an unrestrained pro-inflammatory phenotype that promotes Af invasion. Specific aim 1 utilizes in vitro and in vivo experiments to investigate the concept that ferroptosis is dictated by mɸs polarization state and contributes to the inability of transplant mɸs to mitigate Af infection and studies the role of iron lowering agents and anti-ferroptotic drugs to decrease fungal invasion. Specific aim 2 uses state-of-art omics techniques to define iron induced Af proteases and tests the concept that fungal protease inhibition can mitigate ferroptosis and improve outcomes in the tracheal transplant model. Specific aim 3 studies the ability of alveolar mɸs isolated from human LTRs compared to non-lung transplants to kill Af conidia and correlates the ability of mɸs to kill conidia with mɸs-polarization state and ferroptosis, using mass cytometry. This aim will provide a direct translatability of the hypothesis that iron overload induces ferroptosis and a pro-inflammatory phenotype that promotes fungal invasion. Successful completion of these studies will allow for the discovery of a fundamental new biology and provide novel targets for the treatment of fungal infections.


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 = $558,367 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	5	4/29/2025	NON-COMPETING CONTINUATION	$502,530
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	5	5/28/2025	NON-COMPETING CONTINUATION	$55,837
														Subtotal = $558,367

Issue Date FY: 2024 ( Subtotal = $557,332 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	4	3/22/2024	NON-COMPETING CONTINUATION	$511,836
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	4	6/17/2024	NON-COMPETING CONTINUATION	$45,496
														Subtotal = $557,332

Issue Date FY: 2023 ( Subtotal = $609,585 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	3	3/27/2023	NON-COMPETING CONTINUATION	$609,585
														Subtotal = $609,585

Issue Date FY: 2022 ( Subtotal = $634,716 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	2	3/9/2022	NON-COMPETING CONTINUATION	$571,242
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	2	6/15/2022	NON-COMPETING CONTINUATION	$63,474
														Subtotal = $634,716

Issue Date FY: 2021 ( Subtotal = $592,966 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	1	4/2/2021	NEW	$533,668
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	1	7/30/2021	NEW	$59,298
														Subtotal = $592,966

Grand Total All Awards = $2,952,966

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A critical role for macrophage ferroptosis in promoting fungal invasion in lung transplant recipients

Award Number: R01HL157414

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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