Discovery of novel drug-resistance genes involved in lipid regulation of cell membrane structure and their impact in canine leishmaniasis treatment failure

发现参与细胞膜结构脂质调节的新型耐药基因及其对犬利什曼病治疗失败的影响

• 批准号: RGPIN-2017-04480
• 负责人: FernandezPrada, Christopher
• 金额: $ 3.79万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761945
• 关键词: Discovery; novel; drug; resistance; genes

Canine leishmaniosis (CanL) is a parasite-borne disease mainly caused by Leishmania infantum. Life-threatening L. infantum infects domestic and wild dogs that subsequently develop different clinical presentations ranging from mild presentations to fatal disease. Furthermore, these infected dogs act as a major reservoir and foci of transmission of resistant Leishmania strains to humans. This dangerous zoonotic disease is increasingly affecting countries where it was previously unknown or had been eradicated for a long time. Traditionally, CanL threatened canine species in Europe and South America. However, alarming evidences point to the introduction of this fatal zoonotic disease into the canine populations of Canada and the United States. Despite many vaccine-development efforts have been carried during the last decade, none of has raised as a true alternative to chemotherapy in dogs. The elevated cost of these treatments (an average of $6 000 USD), has triggered unethical dog culling as the only solution to tackle the disease in many endemic countries. In the absence of new drugs introduced in the recent years, current CanL antileishmanials are restricted to only two drugs, old-fashioned antimonial derivatives and antitumor-drug miltefosine. While it is true they are still effective against sensitive Leishmania populations that have never been put in contact with them, their massive use during the last years, coupled to the high ability of these parasites to adapt and survive external stress (including drug pressure), has triggered the rapid emergence and spread of highly resistant populations that are easily transmitted from animals to humans, and vice versa. An additional problem is current antileishmanials have neither well-defined mechanism of action nor mechanism of resistance. Interestingly, the two main drugs currently used for treating CanL, as well as the strongest second line alternative (amphotericin B), seem to induce resistance in Leishmania through major changes in the composition of parasite's cellular lipids and alteration of its cellular membrane fluidity. The here-proposed Research Program aims to discover and investigate novel lipid-related molecular characters responsible for the development of drug resistance in Leishmania. Since such knowledge is currently lacking, our findings will be essential for the development of novel treatments based on experimental molecules that target and/or interact with membrane components. We truly expect the outcomes and knowledge generated in this Research Program, in addition to train highly qualified veterinary-parasitology researchers, will positively impact on future CanL treatment and control by reducing the numbers of slaughtered dogs, dog suffering, resistance emergence, clinical relapse and zoonotic-transmission risk to humans.

犬利什曼病（CanL）是一种主要由婴儿利什曼原虫引起的寄生虫传播疾病。危及生命的湖幼犬感染家犬和野狗，随后出现不同的临床表现，从轻微的表现到致命的疾病。此外，这些受感染的狗作为耐药利什曼原虫株传播给人类的主要储存库和疫源地。这一危险的人畜共患疾病正在越来越多地影响到以前不知道或已经根除很长时间的国家。传统上，CanL威胁欧洲和南美洲的犬类物种。然而，令人震惊的证据表明，这种致命的人畜共患疾病已传入加拿大和美国的犬种群。尽管在过去的十年中进行了许多疫苗开发工作，但没有一种疫苗被认为是狗化疗的真正替代品。这些治疗费用的上涨（平均6000美元），引发了不道德的狗扑杀，成为许多流行国家解决疾病的唯一解决方案。由于近年来没有推出新药，目前的CanL抗利什曼病药物仅限于两种药物，即老式的锑衍生物和抗肿瘤药物米替福新。虽然它们对从未接触过的敏感利什曼原虫种群仍然有效，但在过去几年中，它们的大量使用，加上这些寄生虫适应和生存外部压力（包括药物压力）的高能力，引发了高耐药性种群的迅速出现和传播，这些种群很容易从动物传播到人类，反之亦然。另一个问题是，目前的反利什曼病既没有明确的作用机制，也没有抵抗机制。有趣的是，目前用于治疗CanL的两种主要药物，以及最强的二线替代药物（利什曼菌素B），似乎通过寄生虫细胞脂质组成的重大变化和细胞膜流动性的改变诱导利什曼原虫的耐药性。 这里提出的研究计划旨在发现和调查负责利什曼原虫耐药性发展的新的脂质相关分子特征。由于目前缺乏这种知识，我们的研究结果对于开发基于靶向和/或与膜组分相互作用的实验分子的新型治疗方法至关重要。我们真诚地希望，除了培养高素质的兽医寄生虫学研究人员外，本研究计划产生的成果和知识将通过减少屠宰犬的数量、犬的痛苦、耐药性出现、临床复发和人畜共患病传播风险，对未来的CanL治疗和控制产生积极影响。