Hypoxia Inducible Factor-1α Limits Aspergillus fumigatus Invasion in the Rejecting Airway Allograft.

Abstract

The purpose of this study was to evaluate the efficacy of exogenous up regulation of hypoxia inducible factor (HIF)-1α to reduce Aspergillus fumigatus invasion in the allograft. Background/Methods:Aspergillus fumigatus is an increasing cause of pulmonary disease after lung transplantation. Using an orthotopic tracheal transplant model, we showed that Aspergillus invasion correlated with progressive ischemia and that it could be attenuated by using a Tie2+ von-Hippel Lindau (VHL) knockdown mouse as the transplant recipient.1,2 The VHL-protein is responsible for degrading HIF-1α. In this study, we evaluated the effect of exogenously up regulating HIF-1α, using an adenoviral vector and iron chelator therapy (deferasirox (DFX) and deferoxamine (DFO)), on A. fumigatus invasion. Fungal burden and invasion were graded histopathologically (0-4 scale).1,2 Blood perfusion and tissue O2-tension were measured as previously described.1,2 In our gene therapy experiments, donor trachea were infected with AdCA5, which encodes a modified form of HIF-1α with mutations that inhibit degradation, and compared this group to trachea infected with AdLacZ, a vector that encodes E. coli beta-galactosidase. For our chelator studies mice were treated with DFX, DFO or a saline control. Results: Mice treated with AdCA5, DFO and DFX maintained a higher level of perfusion through day 12 post-transplantation compared to controls. AdCA5 treated animals had a significantly lower level of invasion compared to animals treated with AdLacZ (0.75 vs. 2.2, respectively, p < 0.05). DFX also reduced the invasion of A. fumigatus (0.75 vs. 2.0, respectively, p > 0.05), but this difference was not significant. In contrast, animals treated with DFO showed a non-significant trend toward deeper Aspergillus invasion than control animals (1.7 vs. 1.0, respectively, p > 0.05). Conclusions: HIF-1α up regulation through adenoviral gene therapy or DFX treatment reduced the depth of A. fumigatus invasion in the rejecting allograft. DFO therapy was associated with deeper invasion, which may be explained by the mould's ability to use DFO as an iron source.3 Results from this work may have an important positive impact, providing new targets for preventative and therapeutic interventions for Aspergillus infection.