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

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $557,332

## Abstract

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 pr...

## Key facts

- **NIH application ID:** 10815705
- **Project number:** 5R01HL157414-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Joe L Hsu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $557,332
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815705

## Citation

> US National Institutes of Health, RePORTER application 10815705, A critical role for macrophage ferroptosis in promoting fungal invasion in lung transplant recipients (5R01HL157414-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10815705. Licensed CC0.

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