Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation
Joe L. Hsu1,2, Olga V. Manouvakhova2, Karl V. Clemons3,4, Mohammed Inayathullah5, Allen B. Tu2, Raymond A. Sobel6,7, Amy Tian2, Hasan Nazik3,4,8, Venkata R. Pothineni5, Shravani Pasupneti1,2, Xinguo Jiang2, Gundeep S. Dhillon1, Harmeet Bedi1, Jayakumar
Rajadas1,5, Hubertus Haas9, Laure Aurelian10, David A. Stevens3,4 and Mark R. Nicolls1,2,*
RESEARCH ARTICLE FUNGAL INFECTIONS
Science Translational Medicine 21 Feb 2018:
Vol. 10, Issue 429, eaag2616
DOI: 10.1126/scitranslmed.aag2616
Article

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.

Abstract
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 (ΔsreA/ΔcccA) 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.

http://stm.sciencemag.org/content/10/429/eaag2616?rss=1

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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