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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

基本信息

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
项目类别：
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

项目摘要

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，严重感染会导致贫血甚至死亡