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（CanL）是一种主要由幼利什曼原虫引起的寄生虫传播疾病。危及生命的婴儿乳杆菌感染家养和野狗，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，这些受感染的狗是耐药利什曼原虫毒株向人类传播的主要宿主和疫源地。这一危险的人畜共患疾病正日益影响到以前不知道或已被消灭很长时间的国家。传统上，CanL威胁着欧洲和南美的犬类物种。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类种群。尽管在过去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。这些治疗的高昂费用（平均为6000美元）引发了不道德的扑杀狗，这是许多流行国家应对该疾病的唯一解决方案。由于近年来缺乏新药物的引入，目前CanL的抗利什曼动物仅限于两种药物，老式的锑衍生物和抗肿瘤药物米特福辛。虽然它们确实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，引发了高度耐药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，目前的抗利什曼动物既没有明确的作用机制，也没有明确的耐药性机制。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（两性霉素B），似乎通过改变寄生虫细胞脂质组成和改变其细胞膜流动性，诱导利什曼原虫产生耐药性。***在此提出的研究计划旨在发现和研究利什曼原虫耐药发展的新的脂质相关分子特征。由于目前缺乏这样的知识，我们的发现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治疗方法至关重要。除了培养高素质的兽医寄生虫学研究人员外，我们真心希望这项研究项目产生的成果和知识，将通过减少被屠宰的狗的数量、狗的痛苦、耐药性的出现、临床复发和人畜共患疾病向人类传播的风险，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.