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

描述(由申请者提供)：这个项目是一个K08指导的职业临床科学家奖，专注于促进烟曲霉入侵的信号，一种普遍存在的霉菌，导致侵袭性肺曲霉病(IPA)，每年导致20万例严重感染。在肺移植中，侵袭性烟曲霉菌感染可引起呼吸道吻合口并发症和IPA，死亡率高达80%。曲霉通过血管侵入、血栓形成和抗血管生成因子的产生来建立和适应严重缺氧的微环境，这可能有助于其毒力。 移植的肺特别容易受到缺血的影响，因为只有 在移植过程中，不要常规地进行一次全身动脉重建。因此，与曲霉菌感染协同作用的缺血是一种独特而关键的宿主病原体因素。使用一种新的小鼠气管移植模型，我们发现随着同种异体气管移植物经历渐进性排斥反应介导的缺血，曲霉菌变得更具侵袭性。上调内皮细胞缺氧诱导因子(HIF)-1a(一种血管生成和血管修复的刺激因子)限制了霉菌的入侵。在初步研究中，我们阐明了HIF-1�在修复微血管损伤中的假设作用，它改善了微血管灌流，减少了组织铁超载(弥漫性微血管出血，即从血红素分解中释放的铁)，从而阻止铁超载，铁超载是曲霉入侵的假定刺激因素，也是真菌生长的关键底物。在本提案中，我们定义了HIF-1a 作为观察到的曲霉侵袭减弱的关键媒介。在特定的目标1中，我们将重点放在宿主上，因为我们研究了调节宿主HIF-1a和嫁接铁超载对曲霉入侵的影响。两个子目标评估这些宿主因素：目的1a：确定内皮HIF-1a如何减轻曲霉菌的侵袭，检查组织失活和移植物铁超载的贡献；以及目标1b：确定移植物铁超载在促进曲霉侵袭中的作用。针对特定目的2，我们聚焦于病原菌，利用高度特异的血管生成细胞、转基因小鼠标记物，研究烟曲霉菌对宿主微血管修复的影响。随着所提出的研究的成功结果，我们预计将得出强有力的结论，即内皮细胞HIF-1a上调可以调节烟曲霉菌的侵袭，这将在降低曲霉相关侵袭性感染的风险方面具有重要的治疗意义，并阐明烟曲霉菌致病的基本生物学原理。这一结果将为更多的多学科合作交流创造机会，以评估潜在的信号机制，并开发新的治疗策略来提高肺移植后的存活率。

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.