Hypoxia Adaptation and Fungal Virulence of Aspergillus fumigatus

描述(申请人提供)：我们研究的长期目标是确定最常见的人类空气传播真菌感染病原体烟曲霉菌的致病机制。由于烟曲霉菌引起的疾病发病率持续上升，死亡率保持在50%左右，因此需要对这些感染的病理生理学有新的认识。阐明烟曲霉菌致病的机制对于确定新的治疗策略以改善患者预后具有很大的希望。在之前的资助期间，我们在侵袭性肺曲霉病(IPA)模型中发现低氧、低氧水平是感染部位微环境的关键组成部分。我们的数据表明，低氧导致宿主损伤和不良的IPA疾病结局。这些观察结果与许多人类疾病的数据一致，这些疾病将缺氧与负面治疗结果联系在一起。因为我们目前还不知道低氧如何影响真菌-宿主相互作用的结果，这是一个需要知道的问题，因为低氧和糟糕的人类疾病结果之间存在显著的关联。这一更新建议的目的是确定烟曲霉菌低氧适应的分子机制，并测试改善IPA预后的新的氧气介导的治疗方法。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的结局。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实现。在目标1中，我们将确定一个新的依赖于srbA的转录因子srbB参与一种新的低氧介导的铁摄取机制的机制，这是真菌毒力所必需的。在目标2中，我们将确定之前未知的srbA介导的真菌碳分解代谢抑制在低氧适应和真菌毒力中的作用。在目标3中，我们以令人兴奋的初步数据为基础，表明通过抑制srbA遗传网络来操纵体内氧气肺含量可以改善IPA的结果。这项建议中的实验的成功完成将对影响真菌低氧适应的机制产生新的见解，对真菌毒力的机制产生新的见解，并开发一种新的非侵入性治疗方法来改善IPA的结果。这些拟议的研究预计将是一系列研究的一部分，这些研究将探索和定义在了解真菌如何适应缺氧方面的巨大治疗机会。

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.