Development of a rodent model for anthelmintic testing against multidrug resistant hookworms

钩虫是人和动物的严重寄生虫，严重感染会导致贫血甚至死亡 和弱势群体。近5亿人感染钩虫，主要是在发展中国家， 缺乏卫生基础设施的国家。犬钩虫是最重要的胃肠道寄生虫 狗。钩虫可以用几种驱虫药来控制，在没有疫苗的情况下， 是唯一能控制钩虫感染的方法然而，大量使用驱虫药导致了 对用于治疗家畜寄生线虫的所有主要驱虫药产生遗传抗性。 预计治疗人类的驱虫剂的使用增加会导致人类的驱虫剂耐药性（AR）。 还有钩虫事实上，在赛狗中大量使用驱虫剂导致了 多药耐药（MDR）犬钩虫（犬钩虫）。这些MDR分离株对所有 美国批准用于犬的驱虫药类别。最近，MDR钩虫已经从 灰狗进入一般宠物狗种群，并预计在未来继续这种传播。不仅 MDR钩虫是否会对治疗感染犬的能力产生负面影响，它们也会严重限制治疗 人畜共患病钩虫感染的选择，如皮肤幼虫移行症，嗜酸性肠炎， 弥漫性单侧亚急性视网膜神经炎。因此，迫切需要开发新药来治疗 MDR钩虫感染。驱虫药的开发需要成虫寄生虫来测试潜力 化合物的体外活性，以及感染宿主以测试潜在药物的功效。这受到以下因素的阻碍： 缺乏钩虫感染的小动物模型来测试新药。犬钩虫 目前只在狗身上使用，这使得驱虫药的开发和测试成本高， 有问题因此，我们提出了一个双管齐下的方法来开发一个啮齿动物模型的犬 钩虫感染在目标1中，我们将在接种前和接种过程中使用药物抑制潜在啮齿类宿主的免疫功能。 感染，以确定动物是否允许MDR钩虫感染。我们还将测试 免疫缺陷啮齿类动物对A.犬的在目标2中，我们将使用啮齿动物模型来测试 目前的驱虫药作为原理的证明。犬钩虫感染的小动物模型将大大 促进有效对抗MDR蠕虫的驱虫药的开发，并将提供对 在适用于人类钩虫感染的钩虫中发展AR。

Hookworms are serious parasites of humans and animals, causing anemia and even death in heavy infections and vulnerable populations. Nearly 500 million people are infected with hookworms, primarily in developing countries lacking sanitation infrastructure. Canine hookworms are the most important gastrointestinal parasite of dogs. Hookworms can be controlled using several anthelmintics, which in the absence of a vaccine, remain the only available control for hookworm infections. However, heavy use of anthelmintics has led to the development of genetic resistance to all the major anthelmintics used to treat parasitic nematodes in livestock. Increased use of anthelmintics to treat humans is predicted to lead to anthelmintic resistance (AR) in hookworms as well. Indeed, heavy use of anthelmintics in racing greyhounds has led to the emergence of multidrug resistant (MDR) canine hookworms (Ancylostoma caninum). These MDR isolates are resistant to all classes of anthelmintics approved for use in dogs in the US. Recently, MDR hookworms have spread from greyhounds into the general pet dog population and are predicted to continue this spread in the future. Not only will MDR hookworms negatively affect the ability to treated infected dogs, they will also severely limit treatment options for zoonotic hookworm infections in humans such as cutaneous larva migrans, eosinophilic enteritis and diffuse unilateral subacute neuroretinitis. Therefore, there is an urgent need to develop new drugs to treat infections with MDR hookworms. Development of anthelmintics requires adult parasites to test potential compounds for activity in vitro, and infected hosts to test the efficacy of potential drugs. This is hampered by the lack of a small animal model for hookworm infections in which to test new drugs. Ancylostoma caninum can currently only be maintained in dogs, making anthelmintic development and testing costly and ethically problematic. Therefore, we propose a two-pronged approach to developing a rodent model for canine hookworm infection. In Aim 1, we will use drugs to immunosuppress potential rodent hosts before and during infection to determine if the animals can be permissive to MDR hookworm infection. We will also test immunodeficient rodents for their ability to host A. caninum. In Aim 2, we will use the rodent model to test current anthelmintics as a proof of principle. A small animal model of canine hookworm infection would greatly facilitate the development of anthelmintics effective against MDR worms and would provide insights into the development of AR in hookworms that are applicable to hookworm infections of humans.