Understanding drug resistance in multicellular parasites

了解多细胞寄生虫的耐药性

• 批准号: RGPIN-2017-04417
• 负责人: Dent, Joseph
• 金额: $ 1.89万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=649026
• 关键词: Understanding; drug; resistance; multicellular; parasites

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.

我们的研究计划的目标是开发工具，使加拿大的羊和牛生产者能够更好地应对寄生蛔虫感染，这种感染通常会降低其牲畜的健康和盈利能力。放牧牲畜经常感染寄生的胃肠道蛔虫，从而污染牧场。由胃肠道蛔虫引起的疾病从轻度（降低生长和盈利能力）到严重（导致牲畜死亡）不等。直到最近，生产者还相信他们可以用廉价、有效的除虫药物成功地治疗蛔虫寄生虫，其中最广泛使用的药物之一是伊维菌素。伊维菌素在控制人类和牲畜寄生虫感染方面的重要性在2015年诺贝尔奖中得到了体现，这一奖项授予了发现它的研究人员。不幸的是，寄生虫正在迅速形成对伊维菌素的耐药性，有可能使通过使用伊维菌素取得的卫生成果发生逆转。如果生产者使用伊维菌素治疗感染了耐药寄生虫的牲畜，动物将继续遭受寄生虫的折磨，生产者将浪费时间和金钱在一种无效的药物上。一种便宜、方便的诊断测试将大大提高生产者的能力：1)选择最有效的治疗方法；2)以尽量减少耐药性的延续和传播的方式管理畜群。开发这样的测试需要了解伊维菌素耐药性的遗传基础。由于对生活在羊或牛胃里的寄生虫进行实验具有挑战性，我们研究了一种很容易在实验室中培养的蛔虫——秀丽隐杆线虫的耐药性。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的特定遗传变化。我们从秀丽隐杆线虫身上学到的东西通常也适用于寄生蛔虫；寄生虫具有相似的抗性基因，这些基因以相似的方式改变以引起抗性。我们最近发现了一种基因dyf-7，它可以发生突变，使秀丽隐杆线虫和绵羊寄生虫弯曲血蜱对伊维菌素产生抗药性。然而，我们有理由相信还有许多其他基因参与了耐药性，我们将在秀丽隐杆线虫中发现这些基因。我们发现的基因将被纳入寄生虫耐药性的基因测试，这将有助于保存伊维菌素保护动物和人类健康的遗产。