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

曲霉是环境中常见的真菌，常见于盆栽植物和空调管道中。曲霉产生大量的空气孢子，这些孢子随气流扩散。孢子很小，吸入后可以到达人体肺的末端。这通常并不危险，因为白细胞能够有效地杀死它们。然而，白细胞缺乏或异常的患者无法杀死在体内发芽和生长的孢子，从而导致一种称为侵袭性曲霉菌病的疾病。曲霉可以从肺部进入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，10名感染者中有9人死亡。诊断是困难的，并且是在显著的真菌生长之后，因此需要积极的治疗来阻止感染。只有少数几种抗真菌药物可用。它们作用于真菌细胞壁或细胞膜，目的是杀死真菌而不伤害病人。不幸的是，它们的效果各不相同，尤其是对曲霉。它们对肝脏有毒，并经常与其他药物发生交叉反应。此外，一些曲霉种类正以与细菌对抗生素产生耐药性相同的方式对这些化合物产生耐药性。因此，迫切需要针对曲霉感染的新疗法。我的工作已经确定了曲霉基因，它可以通过感知pH值（氢离子浓度）在小鼠肺内生长，并相应地适应。其中两个基因，palH和palI，介导真菌细胞膜上的ph感应。如果palH和palI功能可以在实验中受损，真菌的生长可能是可以预防的。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感应，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。控制小鼠真菌pH反应的第三个基因是pacC，它在pH？感应调节适当的真菌反应。确定pacC控制下的功能或pacC上游的功能将为干扰这一重要的真菌适应机制提供进一步的机会。

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.