Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation

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Science Translational Medicine  21 Feb 2018:
Vol. 10, Issue 429, eaag2616
DOI: 10.1126/scitranslmed.aag2616

Irons in the fire

Although transplantation is a lifesaving therapy, patients receiving new organs are at serious risk for invasive, potentially fatal infections. Aspergillus fumigatus is a particularly common and troublesome fungal pathogen, but its ability to invade transplant tissues is poorly understood. To evaluate this property, Hsu and colleagues infected transplants in mice. Bleeding, caused by damage to small vessels in grafted airways, led to increased tissue iron, a known growth factor for Aspergillus. Increased tissue iron is a newly identified risk factor for transplant damage by microorganisms. Therapies in development that block iron and protect blood vessels may extend the life of organ recipients.


Invasive pulmonary disease due to the mold Aspergillus fumigatus can be life-threatening in lung transplant recipients, but the risk factors remain poorly understood. To study this process, we used a tracheal allograft mouse model that recapitulates large airway changes observed in patients undergoing lung transplantation. We report that microhemorrhage-related iron content may be a major determinant of A. fumigatus invasion and, consequently, its virulence. Invasive growth was increased during progressive alloimmune-mediated graft rejection associated with high concentrations of ferric iron in the graft. The role of iron in A. fumigatus invasive growth was further confirmed by showing that this invasive phenotype was increased in tracheal transplants from donor mice lacking the hemochromatosis gene (Hfe−/−). The invasive phenotype was also increased in mouse syngrafts treated with topical iron solution and in allograft recipients receiving deferoxamine, a chelator that increases iron bioavailability to the mold. The invasive growth of the iron-intolerant A. fumigatus double-knockout mutant (ΔsreAcccA) was lower than that of the wild-type mold. Alloimmune-mediated microvascular damage and iron overload did not appear to impair the host’s immune response. In human lung transplant recipients, positive staining for iron in lung transplant tissue was more commonly seen in endobronchial biopsy sections from transplanted airways than in biopsies from the patients’ own airways. Collectively, these data identify iron as a major determinant of A. fumigatus invasive growth and a potential target to treat or prevent A. fumigatus infections in lung transplant patients.

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