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

项目摘要 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， 感染全球超过10亿人，保守估计导致1400万人残疾， 调整后的生命年数（DIFFERS）。这些毁灭性病原体造成的发病率和死亡率 组织良好的大规模药物管理局（MDA）计划部分减少了依赖于持续的 有限的驱虫药组合的有效性。阿维菌素是一种广泛使用（最近受到称赞）的药物， 广谱驱虫药是这种有限的化疗药物不可或缺的组成部分， 阿森纳官方人类批准的阿维菌素制剂，伊维菌素，是治疗许多 寄生线虫感染，如淋巴丝虫病（LF），被认为是一种“基本药物”， 世界卫生组织。阿维菌素抗性的前景对线虫未来的成功构成严重威胁 控制程序。这些前景已经在兽医领域实现， 阿维菌素的使用，预计随着选择压力的增加，它将在人类医学中实现 由于MDA覆盖范围的扩大。阿维菌素抗性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抗性和延长 这一关键药物类别的寿命。尽管对紧迫性达成了共识，但对遗传和 阿维菌素抗性的分子决定因素。人体线虫的实验难题 寄生虫需要开发新的方法来发现和验证相关的标志物， 阻力我们建议利用强大的模式线虫秀丽隐杆线虫系统地 询问阿维菌素抗性的复杂遗传决定因素。这一模式对于 了解寄生虫对驱虫药的耐药性，包括谷氨酸门控氯离子的鉴定 渠道作为目标的阿维菌素。我们的中心假设是C。秀丽线虫可以用来识别 在医学上重要的人类寄生虫中预测阿维菌素抗性的遗传基因座。建立 机械保守，推定的遗传标记确定在C。elegans将通过实验验证， 媒介传播的人丝虫寄生虫马来丝虫，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的发现， 验证寄生虫相关的驱虫剂抗性机制。

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.