HIF-1 mediated vascular integrity limits Aspergillus invasion in airway rejection

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): This project is a K08 mentored career clinical scientist award that focuses on signals that promote Aspergillus fumigatus invasion, a ubiquitous mould that causes invasive pulmonary aspergillosis (IPA) resulting in >200,000 cases of serious infection yearly. In lung transplants, invasive A. fumigatus infections cause airway anastomotic complications and IPA with a morality rate as high as 80%. Aspergillus establishes and adapts to a severely hypoxic microenvironment by vascular invasion, thrombosis, and the production of antiangiogenic factors, which likely contribute to its virulence. Transplanted lungs are particularly vulnerable to ischemia, as the only solid organ allografts that do not routinely undergo primary systemic arterial restoration during trans- plantation. Thus, ischemia, working in concert with Aspergillus infection is a unique and critical host- pathogen factor. Using a novel murine tracheal transplant model, we found that Aspergillus becomes more deeply invasive as the allograft undergoes progressive rejection-mediated ischemia. Upregulating endothelial hypoxia inducible factor (HIF)-1a (a stimulator of angiogenesis and vascular repair) limited the invasion of the mould. In preliminary studies, we have elucidated a hypothesized role for HIF-1? in repairing microvascular injury, which improves microvascular perfusion and decreases tissue iron overload (from diffuse microvascular hemorrhage, i.e., iron released from heme breakdown), and thus blocks iron overload, a putative stimulus for Aspergillus invasion and a critical substrate for fungal growth. In this proposal, we define HIF-1a as a pivotal mediator for the observed attenuation of Aspergillus invasion. In Specific Aim 1 we focus on the host, as we investigate the effect of modulating host HIF-1a and graft iron overload on Aspergillus invasion. Two subaims evaluate these host factors: Aim 1a: determines how endothelial HIF-1a mitigates Aspergillus invasion, examining the contribution of tissue devitalization and allograft iron overload; and Aim 1b: determines the role of graft iron overload in promoting Aspergillus invasion. For Specific Aim 2, we focus on the pathogen, studying the impact that A. fumigatus has on host microvascular repair, using highly specific angiogenic cell, transgenic murine markers. With successful outcomes of the proposed studies, we anticipate the strong conclusion that A. fumigatus invasion can be modulated by endothelial cell HIF-1a upregulation, which would have significant therapeutic implications in decreasing the risk for Aspergillus-related invasive infections and elucidate fundamental biologic principles underlying A. fumigatus pathogenesis. This result would create the opportunity for greater multidisciplinary collaborative interchange to evaluate underlying signaling mechanisms and the development of novel therapeutic strategies to improve survival after lung transplantation.