Document text
Principal Investigator: Joe L Hsu
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $557,332
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <A fumigatus><A. fumigatus><AD dementia><ARDS><Active Oxygen><Acute><Acute Renal Failure with Renal Papillary Necrosis><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Allogeneic Transplantation><Alveolar Macrophages><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Animals><Antiproteases><Aspergillosis><Aspergillus><Aspergillus fumigatus><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Autoregulation><Biology><Bleeding><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood monocyte><Body Tissues><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchopulmonary Lavage><COPD><CSF-1><Cancers><Cell Culture Techniques><Cell Death><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Clinical><Cognitive Discrimination><Colony-Stimulating Factor 1><Cytometry><Da Nang Lung><Defect><Discrimination><Drugs><Effector Cell><Endopeptidase Inhibitors><Esteroproteases><Exposure to><Fatty Acid Hydroperoxides><Fe chelation><Fe element><Fe overload><Filamentous Fungi><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fluorescence><Fluorescence Activated Cell Sorting Fractionation><Fluorescence-Activated Cell Sorting><Fluorescence-Activated Cell Sortings><Fungus Diseases><GM-CSF><Genes><Graft Rejection><Granulocyte-Macrophage Colony-Stimulating Factor><Hemorrhage><Histamine-Producing Cell-Stimulating Factor><Histologic Grade><Histopathologic Grade><Homeostasis><Homologous Transplantation><Host Defense><Human><Immune><Immunes><Immunity><Immunoblotting><In Vitro><Infection><Inflammatory><Ingestion><Innate Immune Response><Invaded><Iron><Iron Chelation><Iron Overload><Iron chelator><Ischemia-Reperfusion Injury><Label><Laboratories><Life><Lipid Hydroperoxide><Lipid Peroxides><Lipids><Lipoperoxides><Lung Diseases><Lung Grafting><Lung Lavage><Lung Transplantation><M-CSF><Macrophage><Macrophage Colony-Stimulating Factor><Malignant Neoplasms><Malignant Tumor><Marrow Neutrophil><Marrow monocyte><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Medication><Mice><Mice Mammals><Microscopy><Modern Man><Molds><Molgramostin><Morbidity><Morbidity - disease rate><Murine><Mus><Mycoses><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Oranges><Oxidation-Reduction><Oxygen Radicals><Paralysis Agitans><Parkinson><Parkinson Disease><Pathogenesis><Peptidase Inhibitors><Peptidases><Peptide Hydrolase Inhibitors><Peptide Hydrolases><Peptide Peptidohydrolase Inhibitors><Persons><Pharmaceutical Preparations><Phenotype><Physiological Homeostasis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Primary Parkinsonism><Primary Senile Degenerative Dementia><Pro-Oxidants><Procedures><Production><Protease Antagonists><Protease Gene><Protease Inhibitor><Proteases><Proteinase Inhibitors><Proteinases><Proteolytic Enzymes><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Graft><Pulmonary Macrophages><Pulmonary Transplant><Pulmonary Transplantation><Reactive Oxygen Species><Redox><Reperfusion Damage><Reperfusion Injury><Reporter><Reproduction spores><Role><Shock Lung><Spores><Statistical Methods><Stiff lung><TC-GM-CSF><Techniques><Testing><Time><Tissues><Trachea><Trachea Proper><Transgenic Mice><Transplant Recipients><Transplant Rejection><Transplantation><Transplantation Rejection><Tumor-Cell Human GM Colony-Stimulating Factor><Viral Pneumonia><Western Blotting><Western Immunoblotting><acute kidney injury><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><blood loss><bronchopulmonary lavage therapy><cell culture><cell cultures><chronic obstructive pulmonary disorder><clinically actionable><design><designing><disease of the lung><disorder of the lung><drug/agent><emerging pathogen><experiment><experimental research><experimental study><experiments><flow cytophotometry><fungal infection><fungus infection><granulocyte macrophage colony stimulating factor><improved outcome><in vivo><ingest><inhibitor><lipid peroxide><lung disorder><lung transplant><malignancy><monocyte><mortality><nano particle><nano-sized particle><nanoparticle><nanosized particle><necrocytosis><neoplasm/cancer><neutrophil><new pathogen><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel pathogen><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oxidation reduction reaction><pathogen><post-transplant><post-transplantation><posttransplant><posttransplantation><primary degenerative dementia><protein blotting><response><senile dementia of the Alzheimer type><social role><statistic methods><transplant><transplant model><transplant patient><wet lung><windpipe>