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

犬利什曼病是一种主要由婴儿利什曼原虫引起的寄生虫性疾病。危及生命的L.antum感染家犬和野狗，随后出现从轻微症状到致命疾病的不同临床表现。此外，这些受感染的狗是耐药利什曼原虫向人类传播的主要宿主和聚集地。这种危险的人畜共患病正日益影响那些以前不为人所知或已被根除很长时间的国家。传统上，CAIL威胁到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病已传入加拿大和美国的犬类种群。尽管在过去的十年里进行了许多疫苗开发工作，但没有一项作为狗化疗的真正替代方案被提出。这些治疗的高成本(平均6000美元)在许多地方性国家引发了不道德的狗只扑杀，作为应对这种疾病的唯一解决方案。在近年来没有新药推出的情况下，目前的CAIL抗利什曼药物仅限于两种药物，老式的锑衍生物和抗肿瘤药物米替福辛。虽然它们对从未接触过它们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)的高度能力，引发了高度抗药性的种群的迅速出现和传播，这些种群很容易从动物传播给人类，反之亦然。另一个问题是，目前的抗利什曼药物既没有明确的作用机制，也没有明确的抵抗机制。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品(两性霉素B)似乎通过改变寄生虫细胞脂的组成和改变其细胞膜流动性而诱导利什曼原虫产生耐药性。*这里提出的研究计划旨在发现和调查导致利什曼原虫耐药性发展的新的与脂质相关的分子特征。由于目前缺乏这样的知识，我们的发现将对基于靶向和/或与膜组件相互作用的实验分子的新型治疗方法的开发至关重要。我们真诚地期待，除了培训高素质的兽医寄生虫学研究人员外，这项研究计划产生的成果和知识将通过减少屠宰狗的数量、狗的痛苦、耐药性的出现、临床复发和人畜共患传染病的传播风险，对未来的CANL治疗和控制产生积极影响。

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.