Hypoxia Adaptation and Fungal Virulence of Aspergillus fumigatus

描述（由申请人提供）：我们研究的长期目标是确定人类空气传播真菌感染最常见的病原体烟曲霉的发病机制。由于烟曲霉引起的疾病发病率持续上升，死亡率仍接近50%，因此需要对这些感染的病理生理学有新的认识。阐明烟曲霉致病的机制对确定新的治疗策略以改善患者预后有很大的希望。在之前的资助期间，我们确定了缺氧，低氧水平，作为侵袭性肺曲霉病（IPA）模型感染部位微环境的关键组成部分。我们的数据表明，缺氧有助于宿主损伤和IPA疾病预后不良。这些观察结果与许多人类疾病的数据一致，将缺氧与负面治疗结果联系起来。由于我们目前尚不清楚缺氧如何影响真菌-宿主相互作用的结果，鉴于缺氧与人类疾病预后之间的显著关联，这是一个需要知道的问题。本研究的目的是明确烟曲霉缺氧适应的分子机制，并测试新的氧介导治疗方法以改善IPA的预后。我们的中心假设是，抑制缺氧转录因子SrbA介导的遗传网络可以显著改善IPA结果。本研究的中心假设和目标将通过完成三个具体目标来检验和完成。在目标1中，我们将定义一种新的SrbA依赖转录因子SrbB有助于真菌毒力所需的新型缺氧介导的铁摄取机制的机制。在目标2中，我们将定义SrbA介导的真菌碳分解代谢抑制在缺氧适应和真菌毒力中的未知作用。在目标3中，我们建立了令人兴奋的初步数据，表明通过抑制SrbA遗传网络来操纵体内氧肺含量可以改善IPA结果。本实验的成功完成将对影响真菌缺氧适应的机制产生新的见解，对真菌毒力机制产生新的见解，并开发一种新的非侵入性治疗方法来改善IPA结果。这些拟议的研究有望成为一系列研究的一部分，这些研究将探索和定义了解真菌如何适应缺氧的巨大治疗机会。

DESCRIPTION (provided by applicant): The long-term goal of our research is to define the pathogenesis mechanisms of the most common causative agent of human airborne fungal infections, Aspergillus fumigatus. As the incidence of disease caused by A. fumigatus continues to rise and the mortality rate remains near 50%, new insights into the pathophysiology of these infections is needed. Elucidating the mechanisms by which A. fumigatus causes disease has great promise to identify new therapeutic strategies to improve patient outcomes. During the prior funding period we identified hypoxia, low oxygen levels, as a critical component of the infection site microenvironment in models of invasive pulmonary aspergillosis (IPA). Our data suggest that hypoxia contributes to host damage and poor IPA disease outcomes. These observations are consistent with data from many human diseases linking hypoxia with negative therapeutic results. Because we currently do not understand how hypoxia influences the outcome of fungal-host interactions, this is a need to know question given the significant association between hypoxia and poor human disease outcomes. The objective of this renewal proposal is to define molecular mechanisms of A. fumigatus hypoxia adaptation and test novel oxygen mediated therapeutic for improvement of IPA outcomes. Our central hypothesis is that inhibition of the hypoxia transcription factor SrbA mediated genetic network can be achieved to significantly improve IPA outcomes. The central hypothesis and objective of this research will be tested and accomplished by completing three specific aims. In aim 1, we will define the mechanism by which a new SrbA dependent transcription factor SrbB contributes to a novel hypoxia mediated iron uptake mechanism required for fungal virulence. In aim 2, we will define a previously unknown role for SrbA mediated fungal carbon catabolite repression in hypoxia adaptation and fungal virulence. In aim 3, we build on exciting preliminary data suggesting that manipulation of in vivo oxygen lung content through inhibition of the SrbA genetic network improves IPA outcomes. Successful completion of the experiments in this proposal will generate novel insights into mechanisms affecting fungal hypoxia adaptation, new insights into mechanisms of fungal virulence, and development of a new non-invasive therapeutic to improve IPA outcomes. These proposed studies are expected to be part of a continuum of research that will explore and define the tremendous therapeutic opportunities in understanding how fungi adapt to hypoxia.