Dissection of A. fumigatus alkaline adaptation and virulence (with a view to inhibiting fungal growth in vivo)

烟曲霉碱适应和毒力的解剖（以抑制体内真菌生长）

• 批准号: G0501164/1
• 负责人: Elaine Bignell
• 金额: $ 41.35万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0501164%2F1
• 关键词: Dissection; A.; fumigatus; alkaline; adaptation

Aspergillus is a common fungus in the environment, dwelling in pot plants and air conditioning ducts. Aspergillus produces huge numbers of airborne spores which disperse on air currents. The spores are small enough to reach the extremities of the human lung when inhaled. This is not usually dangerous as white blood cells are able to kill them efficiently. However, patients having white blood cell deficiency or abnormality, cannot kill spores which germinate and grow inside the body causing a disease called invasive aspergilloisis. From the lung aspergillus can penetrate the blood vessels and spread to other organs. Invasive aspergillosis affects up to one quarter of bone marrow transplant recipients and leukaemia patients. Around 60,000 people per year become infected worldwide, as many as 9 out of 10 infected patients die. Diagnosis is difficult and comes after significant fungal growth so aggressive treatment is required to stem infections. Only a handful of antifungal drugs are available. They act on the fungal cell wall or cell membrane and are designed to kill the fungus without harming the patient. Unfortunately they have varying effectiveness, particularly against aspergillus. They are toxic to the liver and often cross-react with other medicines. Furthermore, some aspergillus species are developing resistance to these compounds in the same way that bacteria become resistant to antibiotics. There is, therefore, a desperate need for new therapies against aspergillus infection. My work has identified aspergillus genes which allow growth inside a mouse lung by sensing the pH (concentration of hydrogen ions) and adapting accordingly. Two of the genes, called palH and palI, mediate pH-sensing at the fungal cell membrane. If palH and palI function could be impaired experimentally, fungal growth may be preventable. This project will examine how these genes mediate pH-sensing by identifying the proteins they interact with and provide a means for future screening for chemicals which impair their function by blocking the protein-protein interactions. A third gene controlling the fungal pH response in mice is pacC, which acts after pH?sensing to regulate an appropriate fungal response. Identification of functions under pacC control or which act upstream of pacC will provide further opportunities for interfering with this essential fungal adaptation mechanism.

曲霉菌是一种常见的真菌在环境中，居住在盆栽植物和空调管道。曲霉菌产生大量的空气传播的孢子，这些孢子随气流传播。这种孢子很小，当人吸入时，可以到达人的肺部末端。这通常并不危险，因为白色血细胞能够有效地杀死它们。然而，患有白色血细胞缺乏或异常的患者不能杀死在体内发芽和生长的孢子，从而引起称为侵袭性曲霉病的疾病。肺曲霉菌可以穿透血管并扩散到其他器官。侵袭性曲霉病影响多达四分之一的骨髓移植受者和白血病患者。全世界每年约有6万人感染，每10名感染者中就有9人死亡。诊断是困难的，并在显着的真菌生长后，因此需要积极的治疗来阻止感染。只有少数抗真菌药物可用。它们作用于真菌细胞壁或细胞膜，旨在杀死真菌而不伤害患者。不幸的是，它们的效力各不相同，特别是对曲霉菌。它们对肝脏有毒，并且经常与其他药物发生交叉反应。此外，一些曲霉菌物种正在对这些化合物产生耐药性，就像细菌对抗生素产生耐药性一样。因此，迫切需要针对曲霉菌感染的新疗法。我的工作已经确定了曲霉菌基因，它可以通过感知pH值（氢离子浓度）并相应地进行适应来在小鼠肺内生长。其中两个基因，palH和帕利，介导真菌细胞膜的pH传感。如果palH和帕利的功能可以通过实验被削弱，那么真菌的生长是可以预防的。该项目将研究这些基因如何通过识别与它们相互作用的蛋白质来介导pH传感，并为未来筛选通过阻断蛋白质-蛋白质相互作用而损害其功能的化学物质提供一种手段。第三个控制小鼠真菌pH反应的基因是pacC，它在pH？感测以调节适当的真菌反应。鉴定pacC控制下的功能或pacC上游的功能将为干扰这种重要的真菌适应机制提供进一步的机会。