Discovery and validation of avermectin resistance loci in free-living and parasitic nematodes

项目总结 -- 寄生线虫给许多发展中国家带来了巨大的健康和经济负担， 感染了全球超过10亿人，保守地导致1400万人残疾- 每年调整寿命年(DALY)。这些毁灭性的病原体造成的发病率和死亡率 部分受到组织良好的大规模药物管理(MDA)计划的限制，这些计划依赖于持续的 有限的驱虫药组合的疗效。阿维菌素是一个广泛使用(最近受到赞扬)的类别。 广谱驱虫药是这一有限化疗药物不可或缺的组成部分 阿森纳。人类批准的阿维菌素制剂伊维菌素是治疗许多 寄生性线虫感染，如淋巴丝虫病(LF)，被 世界卫生组织。阿维菌素抗药性的前景对线虫的未来成功构成严重威胁 控制程序。这些前景在兽医领域得到了广泛的应用 阿维菌素的使用，预计随着选择压力的增加，阿维菌素将在人类医学中实现 由于扩大了丙二醛的覆盖面。阿维菌素耐药相关等位基因的早期检测 线虫寄生虫种群对于减缓驱虫剂耐药性和扩大 这一关键药物类别的寿命。尽管在紧迫性上达成了共识，但人们对遗传和 阿维菌素耐药性的分子决定因素。人类线虫的实验难治性 寄生虫需要开发新的方法来发现和验证相关的标志物 抵抗。我们建议利用强大的模式线虫秀丽线虫来系统地 询问阿维菌素耐药性的复杂遗传决定因素。这一模式对 了解寄生虫对驱虫药的抗性，包括鉴定谷氨酸门控氯化物 通道作为阿维菌素的靶标。我们的中心假设是线虫可以用来识别 在医学上重要的人类寄生虫中预测阿维菌素耐药性的遗传位点。建立 机制保护，在线虫中识别的假定遗传标记将在 由媒介传播的人类丝虫寄生虫--马来丝虫，是LF的病原体。完成后，这 该项目将提供一个新的统计遗传学工具包和分子管道，用于发现和 寄生虫相关驱虫抗性机制的验证。

Project summary   Parasitic nematodes impose a massive health and economic burden across much of the developing world, infecting over one billion humans worldwide and conservatively resulting in the loss of 14 million disability- adjusted life years (DALYs) per annum. The morbidity and mortality inflicted by these devastating pathogens is partly curtailed by well-organized mass drug administration (MDA) programs that depend on the continued efficacy of a limited portfolio of anthelmintic drugs. Avermectins are a widely used (and recently lauded) class of broad-spectrum anthelmintics that are an indispensable component of this limited chemotherapeutic arsenal. The human-approved avermectin formulation, ivermectin, is a mainstay in the treatment of many parasitic nematode infections such as Lymphatic Filariasis (LF) and is considered an `Essential Medicine' by the WHO. The prospects of avermectin resistance pose a serious threat to the future success of nematode control programs. These prospects have been realized in the veterinary domain following intensive avermectin use, and are predicted to materialize in human medicine with increased selection pressures resulting from expanded MDA coverage. Early detection of avermectin resistance-associated alleles in nematode parasite populations is essential to the goal of slowing anthelmintic resistance and extending the lifespan of this critical drug class. Despite consensus on urgency, very little is known about the genetic and molecular determinants of avermectin resistance. The experimental intractability of human nematode parasites necessitates the development of new approaches to discover and validate relevant markers for resistance. We propose to utilize the powerful model nematode Caenorhabditis elegans to systematically interrogate the complex genetic determinants of avermectin resistance. This model was crucial towards understanding anthelmintic resistance in parasites, including identification of glutamate-gated chloride channels as the target of avermectins. Our central hypothesis is that C. elegans can be used to identify genetic loci that are predictive of avermectin resistance in medically important human parasites. To establish mechanistic conservation, putative genetic markers identified in C. elegans will be validated experimentally in the vector-borne human filarial parasite Brugia malayi, an etiological agent of LF. Upon completion, this project will make available a new statistical genetics toolkit and molecular pipeline for the discovery and validation of parasite-relevant anthelmintic resistance mechanisms.