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Aspergillus Utilizes Extracellular Heme as an Iron Source During Invasive Pneumonia, Driving Infection Severity
Kathryn Michels1, Angelica L Solomon2, Yogesh Scindia2
1Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
Background:
Depriving microbes of iron is critical to host defense. Hemeproteins, the largest source of iron within vertebrates, are abundant in infected tissues in aspergillosis due to hemorrhage, but Aspergillus species have been thought to lack heme import mechanisms. We hypothesized that heme provides iron to Aspergillus during invasive pneumonia, thereby worsening the outcomes of the infection.
Methods:
We assessed the effect of heme on fungal phenotype in various in vitro conditions and in a neutropenic mouse model of invasive pulmonary aspergillosis.
Results:
In mice with neutropenic invasive aspergillosis, we found a progressive and compartmentalized increase in lung heme iron. Fungal cells cultured under low iron conditions took up heme, resulting in increased fungal iron content, resolution of iron starvation, increased conidiation, and enhanced resistance to oxidative stress. Intrapulmonary administration of heme to mice with neutropenic invasive aspergillosis resulted in markedly increased lung fungal burden, lung injury, and mortality, whereas administration of heme analogs or heme with killed Aspergillus did not. Finally, infection caused by fungal germlings cultured in the presence of heme resulted in a more severe infection.
Conclusions:
Invasive aspergillosis induces local hemolysis in infected tissues, thereby supplying heme iron to the fungus, leading to lethal infection.
Insights
Fungal infections like aspergillosis worsen when the fungus, Aspergillus, utilizes heme iron from the host. This heme uptake increases fungal growth, severity, and mortality in invasive pulmonary aspergillosis.
Area of Science:
- Medical Mycology
- Host-Pathogen Interactions
- Iron Metabolism
Background:
- Iron is essential for microbial survival, and host defense mechanisms often involve iron deprivation.
- Aspergillus species, causative agents of aspergillosis, were previously thought to lack heme import mechanisms, despite heme being a rich iron source in vertebrates.
- Hemorrhage in infected tissues, common in aspergillosis, makes hemeproteins abundant and potentially available to the fungus.
Purpose of the Study:
- To investigate the role of heme as an iron source for Aspergillus during invasive pulmonary aspergillosis.
- To determine if heme uptake influences fungal phenotype and pathogenicity.
- To assess the impact of heme availability on infection outcomes in a host-pathogen model.
Main Methods:
- In vitro assessment of heme's effect on fungal phenotype under various conditions.
- Utilizing a neutropenic mouse model of invasive pulmonary aspergillosis.
- Quantifying lung heme iron levels and fungal burden.
- Administering heme and its analogs to infected mice.
Main Results:
- Invasive aspergillosis led to increased heme iron in infected lung tissues.
- Aspergillus cells readily took up heme, resolving iron starvation, enhancing conidiation, and increasing oxidative stress resistance.
- Intrapulmonary heme administration significantly increased fungal burden, lung injury, and mortality in mice.
- Heme administration worsened infection severity, unlike heme analogs or heat-killed Aspergillus.
Conclusions:
- Invasive aspergillosis is associated with local hemolysis, providing heme iron to Aspergillus.
- Heme uptake by Aspergillus contributes to increased fungal burden, tissue injury, and mortality.
- Targeting heme import or availability could be a therapeutic strategy for invasive aspergillosis.
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