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，在严重感染时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 一群狗。钩虫可以使用几种驱虫剂来控制，在没有疫苗的情况下，这些驱虫剂仍然存在 钩虫感染的唯一可用的控制措施。然而，大量使用驱虫剂导致了 对用于治疗家畜寄生线虫的所有主要驱虫剂的遗传抗性的发展。 越来越多的驱虫剂用于治疗人类，预计将导致对驱虫药的耐药性(AR) 钩虫也是。事实上，在赛狗比赛中大量使用驱虫药已经导致了 耐多药(MDR)犬钩虫(犬钩虫)。这些耐多药菌株对所有 美国批准在狗身上使用的驱虫剂的类别。最近，MDR钩虫从 灰狗进入了一般的宠物狗种群，预计未来还会继续这种传播。不仅 多药耐药钩虫是否会对治疗受感染的狗的能力产生负面影响，它们也会严重限制治疗 人畜共患钩虫感染的选择，如皮肤幼虫迁徙、嗜酸性肠炎 弥漫性单侧亚急性神经性视网膜炎。因此，迫切需要开发新的治疗药物。 感染耐多药钩虫。驱虫剂的开发需要成虫测试潜力 化合物的体外活性，以及感染宿主，以测试潜在药物的疗效。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。犬钩虫罐头 目前只在狗身上保持，这使得驱虫剂的开发和测试成本高昂且符合伦理道德 这是个问题。因此，我们提出了一种双管齐下的方法来建立犬的啮齿动物模型。 钩虫感染。在目标1中，我们将使用药物在啮齿动物潜在宿主之前和期间进行免疫抑制。 以确定动物是否可被耐多药钩虫感染。我们还将测试 免疫缺陷的啮齿动物，因为它们有能力寄生犬种。在目标2中，我们将使用啮齿动物模型来测试 目前的驱虫药是原则上的证明。犬钩虫感染的小动物模型将极大地 促进有效对抗MDR蠕虫的驱虫剂的开发，并将提供对 钩虫AR的发展，适用于人体钩虫感染。

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.