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

了解寄生虫休眠在恰加斯病中的分子基础和作用

• 批准号: MR/T015969/1
• 负责人: John Kelly
• 金额: $ 97.93万
• 依托单位: London School of Hygiene & Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT015969%2F1
• 关键词: Understanding; molecular; basis; role; parasite

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.

查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，包括英国在内的欧洲有数千名感染者。这种疾病是由昆虫传播的单细胞寄生虫克氏锥虫感染引起的。在最初的急性期之后，该疾病可以潜伏数十年，然后重新出现为以心脏病和/或消化道组织损伤为特征的慢性疾病。目前的药物是有毒的，而且往往没有疗效。由于人类感染的复杂性和长期性，对疾病病理学和治疗失败原因的调查一直存在问题。最近有报道称T. cruzi具有经历一种休眠形式的能力，这种现象可能在寄生虫持续存在和目前治疗的有限功效方面具有重要作用。触发休眠的机制尚不清楚，了解这一过程是研究界面临的一个重大挑战。克鲁兹基因改造程序，以更好地了解休眠。我们的目标是确定触发这一过程的生化机制，并建立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来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社区的密切联系将确保这些发现快速整合到发现管道中。

项目成果

Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale

组织微域尺度上克氏锥虫慢性感染病灶与肠神经病变的局部关联

• DOI: 10.1101/2021.03.09.434577
• 发表时间: 2021
• 作者: Khan A

Semi-Synthetic Analogues of Cryptolepine as a Potential Source of Sustainable Drugs for the Treatment of Malaria, Human African Trypanosomiasis, and Cancer.

• DOI: 10.3389/fphar.2022.875647
• 发表时间: 2022
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Abacha, Yabalu Z.;Forkuo, Arnold Donkor;Gbedema, Stephen Y.;Mittal, Nimisha;Ottilie, Sabine;Rocamora, Frances;Winzeler, Elizabeth A.;van Schalkwyk, Donelly A.;Kelly, John M.;Taylor, Martin C.;Reader, Janette;Birkholtz, Lyn-Marie;Lisgarten, David R.;Cockcroft, Jeremy K.;Lisgarten, John N.;Palmer, Rex A.;Talbert, Rosemary C.;Shnyder, Steven D.;Wright, Colin W.
• 通讯作者: Wright, Colin W.

Cardiac Abnormalities in a Predictive Mouse Model of Chagas Disease.

• DOI: 10.3390/pathogens12111364
• 发表时间: 2023-11-17
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Francisco AF;Sousa GR;Vaughan M;Langston H;Khan A;Jayawardhana S;Taylor MC;Lewis MD;Kelly JM
• 通讯作者: Kelly JM

Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale.

• DOI: 10.1371/journal.ppat.1009864
• 发表时间: 2021-08
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Khan AA;Langston HC;Costa FC;Olmo F;Taylor MC;McCann CJ;Kelly JM;Lewis MD
• 通讯作者: Lewis MD

Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose.

• DOI: 10.1021/acs.jmedchem.3c01051
• 发表时间: 2023-09-28
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Racane, Livio;Pticek, Lucija;Kostrun, Sanja;Raic-Malic, Silvana;Taylor, Martin Craig;Delves, Michael;Alsford, Sam;Olmo, Francisco;Francisco, Amanda Fortes;Kelly, John M.
• 通讯作者: Kelly, John M.