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

开发用于针对多重耐药钩虫进行驱虫测试的啮齿动物模型

• 批准号: 10569256
• 负责人: JOHN M HAWDON
• 金额: $ 24.23万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569256
• 关键词: Adrenal Cortex Hormones; Adult; Ancylostoma caninum; Anemia; Animal Model; Animals; Anthelmintics; Canis familiaris; Cessation of life; Child; Cutaneous; Dangerousness; Developing Countries; Development; Diffuse; Disease; Dose; Drug Screening; Drug usage; Ethics; Exploratory/Developmental Grant; Food; Future; Goals; Hamsters; Hookworm Infections; Hookworms; Human; Immune system; Immunologic Deficiency Syndromes; In Vitro; Infection; Infrastructure; Intestinal parasite; Jird; Laboratory Animals; Larva Migrans; Link; Livestock; Modeling; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Mus; Nature; Nematoda; Neuroretinitis; Parasites; Parasitic nematode; Persons; Pharmaceutical Preparations; Phylogenetic Analysis; Population; Predisposition; Prevalence; Race; Rattus; Reproduction; Resistance; Rodent; Rodent Model; STAT6 gene; Sanitation; Specificity; Testing; Vaccines; Vulnerable Populations; Water; Zoonoses; canine model; combat; cost; cost effective; efficacy testing; enteritis; gastrointestinal; genetic resistance; high reward; high risk; immunosuppressed; in vitro activity; insight; negative affect; novel; novel therapeutics; permissiveness; programs

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.

钩虫是人类和动物的严重寄生虫，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，主要发生在发展中国家 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 的狗。可以使用几种驱虫药来控制钩虫，在没有疫苗的情况下，这些驱虫药仍然存在 钩虫感染的唯一可用控制方法。然而，大量使用驱虫药导致 对用于治疗牲畜寄生线虫的所有主要驱虫药产生遗传抗性。 预计增加使用驱虫药来治疗人类会导致驱虫药耐药性（AR） 钩虫也是如此。事实上，在赛狗比赛中大量使用驱虫药已导致出现 多重耐药（MDR）犬钩虫（犬钩虫）。这些 MDR 分离株对所有 在美国批准用于狗的驱虫药类别。最近，MDR钩虫已从 灵缇犬已进入普通宠物狗群体，预计未来这种趋势将继续蔓延。不仅 耐多药钩虫会对治疗受感染狗的能力产生负面影响，它们也会严重限制治疗 人类人畜共患钩虫感染的选择，例如皮肤幼虫移行症、嗜酸粒细胞性肠炎 和弥漫性单侧亚急性神经视网膜炎。因此，迫切需要开发新药来治疗 耐多药钩虫感染。驱虫药的开发需要成年寄生虫来测试潜力 化合物的体外活性和感染宿主以测试潜在药物的功效。这受到阻碍 缺乏用于测试新药的钩虫感染小动物模型。犬钩虫 目前仅在狗身上进行维持，使得驱虫药的开发和测试成本高昂且不道德 有问题的。因此，我们提出了一种双管齐下的方法来开发犬类啮齿动物模型 钩虫感染。在目标 1 中，我们将在之前和期间使用药物来抑制潜在的啮齿动物宿主。 感染以确定动物是否容易感染 MDR 钩虫。我们也会测试 免疫缺陷啮齿类动物具有宿主犬曲霉的能力。在目标2中，我们将使用啮齿动物模型来测试 当前的驱虫药作为原则证明。犬钩虫感染的小动物模型将极大地 促进有效对抗 MDR 蠕虫的驱虫药的开发，并将提供对 MDR 蠕虫的深入了解 钩虫中 AR 的开发适用于人类钩虫感染。