OXYGEN SENSING AND ADAPTATION TO HOST TISSUE HYPOXIA IN C. NEOFORMANS

新生隐球菌的氧传感和对宿主组织缺氧的适应

• 批准号: 7446731
• 负责人: PETER J. ESPENSHADE
• 金额: $ 20.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446731
• 关键词: Acquired Immunodeficiency Syndrome; Address; Aerobic Bacteria; Antifungal Agents; Basidiomycota; Binding; Biology; Brain; Cessation of life; Cholesterol Homeostasis; Cryptococcus neoformans; Databases; Developed Countries; Developing Countries; Dissection; Encapsulated; Endopeptidases; Environment; Fission Yeast; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic Screening; Growth; HIV; Homologous Gene; Human; Hypoxia; Immunocompromised Host; Individual; Infection; Laboratories; Lung; Malignant Neoplasms; Mammals; Membrane; Meningoencephalitis; Molecular; Mus; Mycoses; Numbers; Nutrient; Opportunistic Infections; Organ Transplantation; Oxygen; Pathogenesis; Pathway interactions; Peptide Hydrolases; Positioning Attribute; Prevalence; Public Health; Research Personnel; Signal Transduction Pathway; Starvation; Testing; Therapeutic; Tissues; United States; United States National Institutes of Health; Virulence; Virulence Factors; experience; fungus; genetic analysis; genome sequencing; improved; in vivo; mouse model; novel; pandemic disease; pathogen; positional cloning; programs; research study; response; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The HIV pandemic and increases in immunocompromised patients due to cancer or organ transplants have led to a sharp rise in the number of infections by the encapsulated pathogenic fungus, Cryptococcus neoformans. This ubiquitous basidiomycete fungus enters immunocompromised individuals via the lungs and commonly infects the brain, causing meningoencephalitis and death if untreated. The prevalence of AIDS in the United States and developing countries makes a clear understanding of cryptococcal pathogenesis and improved therapeutics a public health imperative. Infection of a mammalian host is not an obligate step in the lifecycle of C. neoformans, yet this fungus has evolved mechanisms to survive in the host environment. Host tissue oxygen averages 3%, far below atmospheric levels of 21%, and levels in the brain can be as low as 1%. Thus, growth of C. neoformans in the host necessitates adaptation to low oxygen. While the requirement for virulence of environmental signal transduction pathways such as thermotolerance and nutrient starvation has been examined in C. neoformans, nothing is known about how this obligate aerobe responds to changes in environmental oxygen . Here, we will identify mechanisms by which C. neoformans senses oxygen and the adaptive gene expression programs that allow infection to progress. Preliminary experiments indicate that the membrane-bound SREBP transcription factor Sre1, which controls cholesterol homeostasis in mammals, functions in an oxygen sensing pathway and is required for low oxygen growth in C. neoformans. Given that infected host tissues are hypoxic, we hypothesize that SRE1 is required for virulence of C. neoformans. In support of this hypothesis, preliminary studies indicate that Sre1 is activated in response to low oxygen (1% - 3%) and that a C. neoformans strain lacking SRE1 shows decreased virulence in a mouse model of infection. Thus, the SREBP pathway in C. neoformans represents a potential therapeutic target for the treatment of this lethal opportunistic infection. Our specific aims are: AIM 1. To determine the requirement of C. neoformans SRE1 for virulence. AIM 2. To test the requirement of the Sre1 activating protease, Zmp1, for virulence. AIM 3. To isolate additional genes required for low oxygen growth in C. neoformans. Using a combination of gene expression profiling, genetic screening, and in vivo virulence studies in mice, we will identify novel virulence factors in C. neoformans. Our studies will provide the first information about how C. neoformans adapts to low oxygen. The HIV pandemic and increases in the number of immunocompromised patients due to cancer or organ transplants have led to a sharp rise in the number of lethal infections due to the pathogenic fungus, Cryptococcus neoformans. In this project, we will identify genes required for adaptation of this pathogen to the low oxygen environment of the host and for progression of fungal infection. These genes represent candidate targets for future anti-fungal therapy.

描述（由申请人提供）：艾滋病毒的流行以及癌症或器官移植导致的免疫功能低下患者的增加，导致包膜病原真菌新型隐球菌感染的数量急剧增加。这种普遍存在的担子菌通过肺部进入免疫功能低下的个体，通常会感染大脑，如果不及时治疗，会导致脑膜脑炎和死亡。艾滋病在美国和发展中国家的流行使得清楚地了解隐球菌发病机制和改进治疗方法成为公共卫生的当务之急。哺乳动物宿主的感染并不是新型隐球菌生命周期中的必然步骤，但这种真菌已经进化出在宿主环境中生存的机制。宿主组织的含氧量平均为 3%，远低于大气中的 21%，而大脑中的含氧量可低至 1%。因此，新型隐球菌在宿主体内的生长需要适应低氧。虽然已经在新型隐球菌中检查了环境信号转导途径（例如耐热性和营养饥饿）的毒力要求，但对于这种专性需氧微生物如何响应环境氧气的变化仍一无所知。在这里，我们将确定新型隐球菌感知氧气的机制以及允许感染进展的适应性基因表达程序。初步实验表明，控制哺乳动物胆固醇稳态的膜结合 SREBP 转录因子 Sre1 在氧传感途径中发挥作用，并且是新型隐球菌低氧生长所必需的。鉴于受感染的宿主组织处于缺氧状态，我们假设 SRE1 是新型隐球菌的毒力所必需的。为了支持这一假设，初步研究表明，Sre1 在低氧 (1% - 3%) 下被激活，并且缺乏 SRE1 的新型隐球菌菌株在小鼠感染模型中显示出毒力降低。因此，新型隐球菌中的SREBP途径代表了治疗这种致命机会性感染的潜在治疗靶点。我们的具体目标是： AIM 1. 确定新型隐球菌 SRE1 的毒力要求。目的 2. 测试 Sre1 激活蛋白酶 Zmp1 的毒力要求。目的 3. 分离新型隐球菌低氧生长所需的其他基因。通过结合基因表达谱、遗传筛查和小鼠体内毒力研究，我们将鉴定新型隐球菌中的新毒力因子。我们的研究将提供有关新型隐球菌如何适应低氧的第一个信息。艾滋病毒大流行以及癌症或器官移植导致的免疫功能低下患者数量的增加，导致由致病真菌新型隐球菌引起的致命感染数量急剧增加。在这个项目中，我们将鉴定这种病原体适应宿主低氧环境和真菌感染进展所需的基因。这些基因代表了未来抗真菌治疗的候选靶点。