The appearance of non-transferrin-bound iron (NTBI) as a consequence of saturated transferrin (Tf) levels in patients undergoing bone marrow transplantation is multifactorial. Chemotherapy-induced tissue damage on the one hand side, causing iron release from apoptotic cells, and chemotherapy-induced bone marrow suppression leading to diminished iron consumption for erythropoiesis on the other hand side as well as chronic transfusion therapy for anemia are among the major contributing factors for iron overload. The existence of NTBI is known to be associated with therapy-related complications, including infections. Nowadays invasive aspergillosis is, in spite of antifungal prophylaxis, still a serious problem with mortality rates ranging up to 70%-90%. The possible interaction of invasive aspergillosis and iron metabolism has been reported.
In this study we specifically assessed the role of NTBI on the in vitro growth of Aspergillus fumigatus (A. fumigatus ; ATCC46645) in the presence of plasma. Therefore the growth of A. fumigatus in cultures containing 10% human plasma and various NTBI levels was explored. This assay revealed that the presence of NTBI, but not high Tf-saturation without NTBI, led to a considerable growth advantage. These findings suppose that A. fumigatus growth depends on the presence of NTBI rather than total iron availability. Correspondingly, addition of sufficient amounts of human apo-Tf to eliminate NTBI prevented A. fumigatus growth. These results clearly show that NTBI only exists and promotes A. fumigatus growth if Tf is saturated and disproves the widely believed notion that that Aspergillus utilizes iron from Tf. In contrast to apo-Tf, iron chelators (e.g. deferiprone or deferoxamine) tested in our in vitro system stimulated, rather than inhibited A. fumigatus growth, despite elimination of NTBI.
To better understand the underlying molecular mechanisms, different A. fumigatus mutant strains with defects in iron acquisition systems are under investigation. Preliminary data indicate that the uptake of NTBI is not solely dependent on siderophore-mediated iron uptake.
In conclusion our findings clearly indicate that NTBI is relevant for fungal growth, at least in vitro in the presence of plasma. Further ongoing experiments aim to clarify whether different clinical A. fumigatus isolates differ in their ability to utilize Tf- bound iron and NTBI. In addition, plasma samples from patients, who had undergone bone marrow transplantation, with already known levels of NTBI, should help to further corroborate the relevance of NTBI for fungal growth in vivo .
Platzbecker: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding.
Asterisk with author names denotes non-ASH members.