Molecular basis of environmental sensing in fungi and protozoan parasites

许多在人类中引起疾病的单细胞真核寄生虫都精妙地适应了它们在宿主中遇到的复杂和动态的环境，以维持它们的生命周期和传播感染。例如，人类疟疾寄生虫恶性疟原虫在人类和蚊子宿主之间切换，在那里它以特定的组织生态位为目标进行复制和繁殖，而致病真菌新生隐球菌入侵大脑，导致真菌性脑膜炎和脑炎。这些适应要求寄生虫能够感知并对其周围环境中存在的各种化学刺激做出反应，目前为止，大多数机制尚不清楚。它们是如何实现这一点的？哪些蛋白质和机制允许寄生虫完成如此复杂的感染周期？这个项目通过研究寄生原生动物和真菌中的候选基因来解决这个问题，这些基因被预测为编码细胞表面通道和受体的生物信息，但目前尚未确定。这些蛋白质在人类中没有同源物，因此对包括疟疾在内的一系列传染病的药物开发具有特别的前景，仅疟疾一年就导致数十万人死亡，抗药性的发展越来越令人担忧。最近基因组数据的爆炸性增长意味着我们可以利用蛋白质序列信息来连接不同生物中的研究，并询问蛋白质的功能和作用机制是否在整个生命树上是保守的。因此，该项目将采取跨学科的方法，使用生化方法在体外调查候选通道和受体的结构和活性，并结合遗传和分子技术研究疟疾和真菌模型系统，以探索和比较它们在寄生虫生命周期中的作用。

Many of the unicellular eukaryotic parasites that cause disease in humans are exquisitely adapted to navigate the complex and dynamic environments that they encounter in their hosts in order to sustain their life cycles and spread infection. For example, the human malaria parasite, Plasmodium falciparum, switches between human and mosquito hosts where it targets specific tissue niches in order to replicate and reproduce, and the pathogenic fungus, Cryptococcus neoformans invades the brain to causes fungal meningitis and encephalitis. These adaptations require the parasite to be able to sense and respond to the various chemical stimuli present in its' surroundings by, as yet, mostly unknown mechanisms. How do they achieve this and which proteins and mechanisms allow parasites to fulfil such complex infectious cycles?This project addresses this question by investigating candidate genes in parasitic protozoa and fungi that are predicted bioinformatically to encode cell-surface channels and receptors, but are currently uncharacterised. These proteins have no homologues in humans, so hold particular promise for drug development for a range of infectious diseases, including malaria, which alone kills hundreds of thousands of people yearly and for which the development of drug-resistance is an increasing concern. The recent explosion in genomic data means we can use protein sequence information to bridge studies in different organisms and ask whether the function and mechanism of action of proteins is conserved across the tree of life. The project will, therefore, have an interdisciplinary approach, using biochemical methods to investigate the structure and activity of candidate channels and receptors in vitro, and malaria and fungal model systems together with genetic and molecular technologies to explore and compare their roles throughout the parasitic lifecycles.