Identifying and Characterising Developmental Regulators of Human Infectious Leishmania

利什曼原虫的物种威胁着全球四大洲的3.5亿人。世界卫生组织估计，目前有1200万人感染，每年新增病例超过100万例。目前尚不存在疫苗，现有的利什曼病治疗方法往往被发病率和严重性不断增加的急性流行病所淹没。人们迫切需要新的治疗方法和疫苗，英国政府已承诺响应世界卫生组织最近的呼吁，进一步支持被忽视的热带病研究。单细胞利什曼原虫在其生命周期中转变为许多不同的形式，以适应非常不同的宿主；从哺乳动物到沙蝇，再通过沙蝇的叮咬回到哺乳动物。只有某些生命周期阶段的利什曼原虫才能在人类体内感染和存活。在这些使寄生虫能够存活的转变过程中，寄生虫的外观、代谢和毒力蛋白发生了重大变化。利什曼原虫的基因表达几乎完全依赖于mRNA的调节。作为对环境变化的反应，特定的寄生虫蛋白结合mRNAs，并将其作为蛋白质生产的靶标，以引导和促进适应。控制这些寄生虫所经历的变化的蛋白质使它们能够适应、在体内生存并感染人类。这些蛋白质对于利什曼原虫感染的毒力和传播是必不可少的。通过表征这些调节蛋白及其下游靶标，我们可以发现利什曼原虫使用什么机制来控制它们的生命周期变化。如果我们能分离并阻止控制面板“调节器”蛋白，我们就能阻止寄生虫在人类身上建立感染。重大发现将为利什曼病研究以及相关寄生虫、恰加斯病和非洲锥虫病引起的疾病提供洞察力。利什曼原虫蛋白与人类蛋白不同，因此我们可以利用这些差异来靶向利什曼原虫特有的发育调节因子，阻断它们的功能，阻止寄生虫的入侵能力。不幸的是，还没有发现利什曼原虫调节蛋白。我建议找利什曼原虫的监管者。生命周期的变化，确定它们是如何发挥作用的，并测试其中是否对寄生虫的生存至关重要。必要的调节剂可以作为潜在的药物靶标来阻止利什曼原虫感染。

Species of Leishmania threaten 350 million people worldwide on four continents. The World Health Organisation estimates 12 million are currently infected and over 1 million new cases occur annually. No vaccine currently exists and available Leishmaniasis treatments are often overwhelmed by acute epidemics that are increasing in occurrence and severity. New treatments and vaccines are desperately needed and the UK government has committed to the World Health Organisation's recent call to further support Neglected Tropical Disease research. The single-cell Leishmania parasite transforms into many different forms during its lifecycle to adapt to very different hosts; moving from mammals to sandflies and back to mammals by sandfly bites. Only Leishmania parasites of certain lifecycle stage forms can infect and survive in humans. Major changes to the parasite's appearance, metabolism and virulence proteins occur during these transitions that enable them to survive. Leishmania gene expression relies almost exclusively upon mRNA regulation. In response to changes in the environment, specific parasite proteins bind mRNAs and target them for protein production to guide and promote adaptation. Proteins that control the changes these parasites go through enable them to adapt, survive in and infect humans. Such proteins are essential for the virulence and spread of the Leishmania parasite infection. By characterising such regulatory proteins and their downstream targets, we can find out what mechanisms the Leishmania parasites use to control their lifecycle changes. If we can isolate and stop control panel "Regulator" proteins, we can block the parasite from establishing an infection in humans. Significant findings would provide insight to Leishmaniasis research as well as diseases caused by related parasites, Chagas Disease and African Trypanosomiasis. Leishmania proteins are different from human proteins; therefore we can exploit these differences to target Leishmania-specific developmental regulators, block their function and block the parasites' ability to invade. Unfortunately, no Leishmania regulator proteins have yet been identified. I propose to find regulators of Leishmania spp. lifecycle changes, identify how they function, and test whether any are essential for parasite survival. Essential Regulators could serve as potential drug targets to block Leishmania parasite infection.