Understanding drug resistance in multicellular parasites

我们研究计划的目标是开发工具，使加拿大羊和牛的生产者能够更好地应对寄生虫感染，这种感染通常会降低他们牲畜的健康和盈利能力。放牧牲畜经常感染肠道寄生虫，污染牧场。胃肠道蛔虫引起的疾病从轻微的、降低生长和盈利能力的疾病，到导致牲畜死亡的严重疾病。直到最近，生产商还相信他们可以用廉价、有效的驱虫药物成功治疗蛔虫寄生虫，其中使用最广泛的药物之一是伊维菌素。2015年诺贝尔奖授予发现伊维菌素的研究人员，反映了伊维菌素在控制人畜寄生虫感染方面的重要性。不幸的是，寄生虫正在迅速产生对伊维菌素的抗药性，有可能逆转通过使用伊维菌素所取得的健康成果。如果生产商使用伊维菌素治疗感染了抗药性寄生虫的牲畜，动物将继续遭受寄生虫的折磨，生产商将在一种无效的药物上浪费时间和金钱。一种廉价、方便的诊断测试将极大地提高生产商的能力，以：1)选择最有效的治疗方法；2)以最大限度地减少耐药性的永久存在和传播的方式管理牛群。要开发这样的测试，需要了解伊维菌素耐药性的遗传基础。*因为对住在羊或牛胃里的寄生虫的实验具有挑战性，我们研究了一种很容易在实验室培养的线虫--秀丽线虫的耐药性。我们寻找对伊维菌素耐药的突变菌株，并确定解释伊维菌素耐药性的特定基因变化。我们从线虫身上学到的东西通常也适用于寄生的蛔虫；寄生虫有相似的抗性基因，这些基因以相似的方式改变以产生耐药性。最近我们发现了一种名为dyf-7的基因，它可以发生突变，使线虫和绵羊寄生虫对伊维菌素产生抗药性，从而证明了这一点。然而，我们有理由相信，还有许多其他与抗性有关的基因，我们将在线虫中识别这些基因。我们发现的基因将被纳入寄生虫抗药性的基因测试中，这将有助于保护伊维菌素保护动物和人类健康的遗产。

The goal of our research program is to develop tools that will allow Canadian sheep and cattle producers to better cope with parasitic roundworm infections that commonly reduce the health and profitability of their stock. Grazing livestock are frequently infected with parasitic gastrointestinal roundworms that contaminate pastures. The disease caused by gastrointestinal roundworms ranges from mild, reducing growth and profitability, to severe, leading to the death of livestock. Until recently, producers were confident that they could successfully treat roundworm parasites with inexpensive, effective de-worming drugs, of which one of the most widely used is ivermectin. Ivermectin's importance in controlling parasite infections in both humans and livestock was reflected in the 2015 Nobel Prize awarded to the researchers who discovered it. Unfortunately, parasites are rapidly evolving resistance to ivermectin, threatening to reverse the health gains achieved through its use. If producers use ivermectin to treat livestock infected with resistant parasites, animals continue to suffer from parasites and the producer will have wasted time and money on an ineffective drug. An inexpensive, convenient diagnostic test would greatly improve the ability of producers to: 1) choose the most effective treatments, and 2) to manage herds in ways that minimize the perpetuation and spread of drug resistance. To develop such a test requires an understanding of the genetic basis of ivermectin resistance.***Because experiments on parasitic worms that live a sheep's or cow's stomach are challenging, we study drug resistance in a roundworm, Caenorhabditis elegans, that can easily be grown in the laboratory. We look for mutant strains that are resistant to ivermectin and identify the specific genetic changes that explain ivermectin resistance. What we learn from C. elegans usually applies to parasitic roundworms as well; parasites have similar resistance genes that are changed in similar ways to cause resistance. This was recently demonstrated by our discovery of a gene, dyf-7, that can mutate to make both C. elegans and the sheep parasite Haemonchus contortus resistant to ivermectin. However, we have reason to believe that there are many other genes involved in resistance, genes that we will identify in C. elegans. The genes we find will be incorporated into a genetic test for resistance in parasites that will help preserve ivermectin's legacy of protecting animal and human health.