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

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.

Aspergillus fumigatus and Aspergillosis in 2019

“…It is tempting to speculate that, in a model analogous to cancer evolution, unabated chronic inflammation induced by prolonged fungal persistence triggers metabolic reprogramming of macrophages and results in nutritional immunity deregulation favoring fungal growth. The predominant role of iron deregulation in the development of IA has been demonstrated recently in a nonneutropenic model of lung transplantation (596) and in the Aspergillus keratitis model (279). These findings support a model of sequential immune defects in phagosome biogenesis and iron homeostasis in phagocytes, leading to invasive Aspergillus growth (Fig.…”

“…18). From the host site, intracellular and extracellular pathways of nutritional immunity, an ancient host defense strategy of iron limitation to pathogens, becomes essential once other immune effector mechanisms are compromised (239,279,596). Accordingly, the relative rarity of IA in patients with congenital neutropenia or aplastic anemia compared to the neutropenic patients with HSCT or acute leukemia implies that deregulated iron and nutrient homeostasis in the latter group of patients facilitates vegetative hyphal development.…”

Novel intermicrobial molecular interaction: Pseudomonas aeruginosa Quinolone Signal (PQS) modulates Aspergillus fumigatus response to iron

“…Bacto agar used for growth studies was obtained from Carolina Biological Supply Co., Burlington, NC. Fe-depleted agar was prepared by formulating potato dextrose agar (PDA) in the presence of ascorbate and ferrozine as we previously described [36]. Cultures were grown at 37 °C on PDA plates containing 1 mM ascorbate (Sigma-Aldrich) and 1 mM ferrozine (Sigma-Aldrich).…”

Iron Homeostasis in the Lungs—A Balance between Health and Disease

“…Patients who underwent lung transplantation showed increased pulmonary iron levels in the allografts after transplantation that possibly contributed to the risk of oxidative stress and lung injury [37,38]. In addition, high iron levels in a tracheal allograft mouse model increased the risk for A. fumigatus invasion, a well-known pathogen causing common respiratory infectious disease in lung transplant recipients [39].…”