Understanding the molecular basis and role of parasite dormancy in Chagas disease

恰加斯病是拉丁美洲最重要的寄生虫感染，影响600万至800万人。此外，由于移民，它正在成为一个全球性的健康问题，成千上万的感染者居住在欧洲，包括英国。该病是由感染由昆虫传播的单细胞寄生虫克氏锥虫引起的。在最初的急性阶段之后，这种疾病可以潜伏数十年，然后以心脏病和/或消化道组织损伤为特征的慢性疾病重新出现。目前的药物是有毒的，而且往往没有疗效。由于人类感染具有复杂的长期性，对疾病病理和治疗失败原因的调查一直存在问题。最近，有报道称克氏锥虫具有一种休眠的能力，这一现象可能对寄生虫的持续存在和目前治疗的有限效果有重要作用。触发休眠的机制尚不清楚，了解这一过程对研究界来说是一个重大挑战。在这个项目中，我们将利用我们在寄生虫成像技术和高通量克氏T.基因改造程序方面取得的进展来更好地了解休眠。我们的目标是确定触发这一过程的生化机制，并确定其在寄生虫生命周期中的生物学作用。这项研究的结果将对治疗发展产生直接影响。我们将提供新的信息，以帮助设计能够杀死休眠和可能代谢静止的寄生虫的药物。我们与全球恰加斯病药物开发界的密切联系将确保将这些发现迅速纳入发现管道。

Chagas disease is the most important parasitic infection in Latin America, affecting 6 - 8 million people. In addition, because of migration, it is becoming a global health problem, with thousands of infected individuals resident in Europe, including the UK. The disease results from infection with the insect-transmitted single-cell parasite Trypanosoma cruzi. Following the initial acute stage, the disease can remain latent for decades before re-emerging as a chronic condition characterised by heart disease and/or digestive-tract tissue damage. Current drugs are toxic and often non-curative. Because of the complex long-term nature of human infections, investigations into disease pathology and the reasons for treatment failure have been problematic. Recently, it has been reported that T. cruzi has the capacity to undergo a form of dormancy, a phenomenon that may have important roles in parasite persistence and the limited efficacy of current therapy. The mechanisms that trigger dormancy are unknown, and understanding the process represents a major challenge to the research community.In this project, we will exploit advances that we have made in parasite imaging technology and high-throughput T. cruzi genetic modification procedures to better understand dormancy. Our goals are to identify the biochemical mechanisms that trigger the process and to establish its biological role in the life-cycle of the parasite. The outcome of this research will have an immediate impact on therapeutic development. We will provide new information to aid the design of drugs that are able to kill parasites that are dormant and probably metabolically quiescent. Our close links with the global Chagas disease drug development community will ensure rapid integration of these findings into the discovery pipeline.