Environmental Oxygen Transitions and Aspergillosis Disease Progression

环境氧转变和曲霉病进展

• 批准号: 10161719
• 负责人: Robert Andrew Cramer
• 金额: $ 52.94万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161719
• 关键词: Acute leukemia; Adrenal Cortex Hormones; Alanine Transaminase; Antifungal Agents; Antifungal Therapy; Aspergillosis; Aspergillus fumigatus; Autoimmunity; Chronic; Collection; Data; Defect; Development; Disease; Disease Outcome; Disease Progression; Dose; Environment; Exhibits; Fungal Genes; Genes; Genetic; Genetic Screening; Genetic Transcription; Growth; Health; Homeostasis; Human; Hypoxia; Immune; Infection; Integration Host Factors; Knowledge; Lead; Lung; Metabolic; Metabolism; Microbial Biofilms; Modeling; Molds; Molecular; Morbidity - disease rate; Mycoses; Names; Natural Immunity; Oxygen; Pathway interactions; Patients; Phenotype; Production; Regulation; Research; Role; Site; Testing; Tissues; Transplant Recipients; Virulence; Work; base; chemotherapy; fitness; flexibility; fungus; genetic effector; graft vs host disease; hematopoietic cell transplantation; improved; in vivo; in vivo imaging; innovation; insight; metabolome; mortality; mutant; novel; novel therapeutics; pathogenic fungus; patient population; response; therapeutic target; transcription factor; transcriptome

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.

项目摘要。 侵袭性曲霉病（IA）是免疫功能低下患者感染性发病和死亡的主要原因， 患者，特别是那些患有急性白血病，造血细胞移植和慢性 移植物抗宿主病和自身免疫的皮质类固醇治疗。尽管抗真菌药物最近取得了进展 然而，对于哪些真菌和宿主因素对治疗后的疾病进展至关重要，仍然知之甚少。 在肺部建立感染。为了缩小这个范围，我们做了两个基本的观察。 知识差距。首先，IA的病原体，烟曲霉，与宿主组织相互作用以产生一种免疫抑制剂。 感染部位的动态氧微环境。第二，A.烟曲霉适应已建立的感染 通过表现出对真菌毒力至关重要的感染位点特异性代谢灵活性来改变微环境。 我们最近将这些适应性改变称为“疾病进展因子”（DPFs），因为它们对于疾病的发生和发展至关重要。 侵袭性疾病的进展，在人类真菌感染的背景下相对不确定。一个令人兴奋 最近的发现是真菌氧反应遗传网络以前未被认识到的作用， 包括响应于氧张力的转变的DPF，SrbA、SrbB和CreA。我们最近的数据 我们假设这种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。这种遗传网络的一个主要效应器，一种未经研究的真菌， 丙氨酸氨基转移酶alaA是本提案目标1中机制研究的重点。我们提出了一个 alaA作为适应氧气所需的代谢转换的关键调节器的模型 真菌疾病进展期间的波动。在目标2中，我们建立了一个新的遗传筛选， 鉴定了四种新的未经研究的真菌转录因子，它们对氧张力的反应至关重要 波动我们将这些新基因命名为ortA-D，它们是氧响应真菌转录因子。一个 我们测试假设和模型的方法的创新之处在于结合了在体内成像， 疾病进展期间感染部位微环境，揭示了对真菌形式的新见解， 在已建立的感染中起作用。因此，在这些研究结束时，我们将定义新的 在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入性霉菌感染的疾病结果。