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

Autor:	Hsu JL; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.; Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA 94304, USA., Manouvakhova OV; Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA 94304, USA., Clemons KV; Infectious Diseases Research Laboratory, California Institute for Medical Research, San Jose, CA 95128, USA.; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA., Inayathullah M; Biomaterials and Advanced Drug Delivery Laboratory, Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94304, USA., Tu AB; Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA 94304, USA., Sobel RA; Veterans Affairs Palo Alto Health Care System, Pathology and Laboratory Service, Palo Alto, CA 94304, USA.; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA., Tian A; Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA 94304, USA., Nazik H; Infectious Diseases Research Laboratory, California Institute for Medical Research, San Jose, CA 95128, USA.; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.; Department of Medical Microbiology, Istanbul University School of Medicine, Istanbul, Turkey., Pothineni VR; Biomaterials and Advanced Drug Delivery Laboratory, Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94304, USA., Pasupneti S; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.; Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA 94304, USA., Jiang X; Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA 94304, USA., Dhillon GS; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA., Bedi H; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA., Rajadas J; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.; Biomaterials and Advanced Drug Delivery Laboratory, Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94304, USA., Haas H; Division of Molecular Biology, Medical University Innsbruck, Innsbruck, Austria., Aurelian L; Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA., Stevens DA; Infectious Diseases Research Laboratory, California Institute for Medical Research, San Jose, CA 95128, USA.; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA., Nicolls MR; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. mnicolls@stanford.edu.; Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA 94304, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2018 Feb 21; Vol. 10 (429).
DOI:	10.1126/scitranslmed.aag2616
Abstrakt:	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 (Δ sreA /Δ cccA ) 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. (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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