Hypoxia Adapatation and Fungal Virulence of Aspergillus fumigatus

描述（由申请人提供）：侵袭性曲霉病（IA）是由霉菌烟曲霉引起的，是一种日益重要的未充分研究的疾病，每年在美国导致3500多人死亡。随着新医疗技术的发展，易感染烟曲霉的患者也在急剧增加。目前，我们对这种常见霉菌引起疾病的机制了解有限。虽然烟曲霉在感染过程中可能会遇到显著的环境胁迫，但真菌如何适应体内感染部位的微环境尚不完全清楚。我们发现烟曲霉在感染过程中会出现明显的缺氧。重要的是，我们已经发现这种霉菌对缺氧的适应是遗传调控的，并且是真菌毒力所必需的。因此，本研究的长期目标是确定这种真菌在免疫功能低下患者中适应缺氧和致病的分子机制。这可能会导致新的IA治疗干预措施的发展。本研究有三个具体目的，旨在确定由甾醇调节元件结合蛋白（SREBP） SrbA介导的缺氧适应的分子机制，SrbA介导烟曲霉的缺氧适应和真菌毒力。在aim 1中，我们将定义SrbA在烟曲霉中被激活的位置和时间，建立烟曲霉SrbA介导的缺氧适应模型的第一部分。在目标2中，我们将识别和描述与SrbA相互作用并可能调节其活性的关键参与者，并将第二层调节层添加到我们的模型中。在目标3中，将鉴定和表征SrbA介导烟曲霉适应缺氧的关键下游效应物。这3个目标的完成将为烟曲霉一种新的毒力特性的机制提供急需的见解，并为首次建立致病霉菌中SREBP信号传导模型奠定基础。这些特定目的的研究也将为未来的研究提供额外的目标，以阐明可能适用于广谱致病性霉菌的缺氧适应机制。公共卫生相关性：随着医疗技术的进步，普通霉菌造成的致命感染正变得越来越普遍。这些感染的治疗选择非常有限，迫切需要新的治疗干预措施。本提案旨在发现新的治疗方案，以治疗由丝状霉菌烟曲霉引起的侵袭性曲霉病。

DESCRIPTION (provided by applicant): Invasive aspergillosis (IA) is caused by the mould Aspergillus fumigatus and is an understudied disease of growing significance that causes over 3,500 deaths in the United States annually. The spectrum of patients susceptible to A. fumigatus infections is also dramatically increasing with the development of new medical technologies. Currently, our understanding of the mechanisms utilized by this common mould to cause disease is limited. Though it is likely that A. fumigatus encounters significant environmental stress during IA, how the fungus adapts to micro-environments found in vivo at sites of infection is not fully understood. We have discovered that A. fumigatus encounters significant hypoxia during infection. Importantly, we have discovered that adaptation to hypoxia is genetically regulated in this mould and required for fungal virulence. Thus, the long-term objective of this proposal is to define the molecular mechanisms utilized by this fungus to adapt to hypoxia and cause disease in immunocompromised patients. This may lead to development of novel therapeutic interventions for IA. This proposal has three specific aims designed to define the molecular mechanism of hypoxia adaptation as mediated by a sterol-regulatory element binding protein (SREBP), SrbA, that mediates hypoxia adaptation and fungal virulence in A. fumigatus. In aim 1, we will define where and when SrbA is activated in A. fumigatus establishing the first part of a model of SrbA mediated hypoxia adaptation in A. fumigatus. In aim 2, we will identify and characterize the key players that interact with SrbA and likely regulate its activity adding the second regulatory layer to our model. In aim 3, the key downstream effectors of SrbA that mediate adaptation to hypoxia by A. fumigatus will be identified and characterized. Completion of these 3 aims will offer much needed insights into the mechanisms of a novel virulence attribute of A. fumigatus and lay the foundation for a model of SREBP signaling in a pathogenic mould for the first time. Investigations in these specific aims will also provide additional targets for future studies to elucidate mechanisms of hypoxia adaptation that may be applicable to a broad-spectrum of pathogenic moulds. PUBLIC HEALTH RELEVANCE: Lethal infections by common moulds are becoming increasingly common with advances in medical technologies. Treatment options for these infections are very limited, and new therapeutic interventions are urgently needed. This proposal seeks to discover new therapeutic options to treat invasive aspergillosis caused by the filamentous mould Aspergillus fumigatus.