Environmental Oxygen Transitions and Aspergillosis Disease Progression

项目摘要。 侵袭性曲霉病(IA)是免疫低下患者感染性发病率和死亡率的主要原因 患者，特别是急性白血病患者、造血细胞移植患者和慢性粒细胞白血病患者 皮质类固醇治疗移植物抗宿主病和自身免疫。尽管最近在抗真菌方面取得了进展 治疗，目前还不清楚哪些真菌和宿主因素是疾病进展的关键 肺部感染的确立。我们对缩小这一范围提出了两个基本观察 知识鸿沟。首先，IA的病原体烟曲霉与宿主组织相互作用产生一种 感染部位的动态氧气微环境。其次，烟曲霉菌适应已建立的感染 通过表现出感染部位特定的代谢灵活性，这对真菌的毒力至关重要。 我们最近将这些适应称为疾病进展因子(DPF)，因为它们对 侵袭性疾病的进展，在人类真菌感染的背景下相对不确定。一场激动人心的 最近的发现是真菌氧反应遗传网络以前没有被认识到的作用，它 包括DPF、SrbA、SrbB和CREA，以响应氧气张力的转变。我们最近的数据领先 我们假设这个氧反应网络调节特定代谢物的产生， 促进和支持真菌疾病的进展。这一遗传网络的一个主要影响因素是一种未被研究的真菌 丙氨酸氨基转移酶Alaa是本方案目标1机制研究的重点。我们提出了一个 AlaA作为氧适应所需代谢转变的关键调节因子的模型 真菌疾病进展过程中的波动。在目标2中，我们建立了一个新的基因屏幕，它具有 确定了四个新的真菌转录因子，这些转录因子对氧紧张反应至关重要 波动。我们将这些新基因命名为氧气响应真菌转录因子Orta-D。一个 我们测试假说和模型的方法的创新之处在于结合了体内成像 疾病进展过程中感染部位的微环境，揭示了对真菌形态和 在已确定的感染中起作用。因此，在这些研究的结论中，我们将定义新的 已建立的感染环境中真菌适应性的分子机制有望揭示新的 治疗机会，以改善这些往往致命的侵袭性霉菌感染的疾病结局。

Project Summary. Invasive aspergillosis (IA) is a major cause of infectious morbidity and mortality in immune compromised patients, particularly those with acute leukemia, hematopoietic cell transplantation, and recipients of chronic corticosteroid therapy for graft versus host disease and autoimmunity. Despite recent advances in antifungal therapies, it remains poorly understood which fungal and host factors are critical for disease progression after establishment of infection in the lung. We have made 2 fundamental observations toward narrowing this knowledge gap. First, the causative agent of IA, Aspergillus fumigatus, interacts with host tissue to generate a dynamic oxygen microenvironment at the site of infection. Second, A. fumigatus adapts to established infection microenvironments by exhibiting infection site-specific metabolic flexibility that is critical for fungal virulence. We recently termed these adaptations “disease progression factors” (DPFs) because they are essential for the progression of invasive disease and relatively undefined in the context of human fungal infections. An exciting recent discovery is the previously unappreciated role of the fungal oxygen response genetic network, which includes the DPFs, SrbA, SrbB and CreA, in responses to transitions in oxygen tension. Our recent data lead us to hypothesize that this oxygen response network regulates the production of specific metabolites that promote and support fungal disease progression. A major effector of this genetic network, an unstudied fungal alanine aminotransferase alaA, is the focus of mechanistic studies in Aim 1 of this proposal. We propose a model whereby alaA functions as key regulator of metabolic transitions required for adaptation to oxygen fluctuations during fungal disease progression. In aim 2, we build off a novel genetic screen which has identified four new unstudied fungal transcription factors that are critical for the response to oxygen tension fluctuations. We have named these new genes ortA-D for oxygen responsive fungal transcription factors. An innovation to our approach to test our hypotheses and models is the incorporation of in vivo imaging of the infection site microenvironment during disease progression that is revealing new insights into fungal form and function in an established infection. Consequently, at the conclusion of these studies, we will have defined new molecular mechanisms of fungal fitness in established infection environments that are expected to reveal new therapeutic opportunities to improve disease outcomes for these too often lethal invasive mold infections.