Emerging benzimidazole resistance in human hookworms

人类钩虫中出现的苯并咪唑耐药性

基本信息

批准号：
9920667
负责人：
MICHAEL CAPPELLO
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-09 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920667
关键词：
Address Adult Africa Africa South of the Sahara Albendazole Anemia Binding Binding Proteins Biology Blood Child Chronic Communicable Diseases Communities Country Data Development Dose Drug Tolerance Drug usage Effectiveness Environment Epidemiology Exposure to Frequencies Gene Expression Gene Frequency Genes Genetic Markers Genetic Structures Genomic DNA Genotype Ghana HIV Health Policy Helminths Hookworm Infections Hookworms Human Impaired cognition In Vitro Individual Institution Intestines Knowledge Laboratories Livestock Malaria Malnutrition Maps Maternal and Child Health Mediating Medicine Methods Molecular Monitor Morbidity - disease rate Municipalities Mutation Necator americanus Nematoda Outcome Parasites Parasitology Pharmaceutical Preparations Population Predisposition Public Health Research Research Personnel Research Training Resistance Resources Risk Sampling School-Age Population Single Nucleotide Polymorphism Soil Spatial Distribution Structure Surveys Testing Treatment Failure Tuberculosis Universities Vulnerable Populations Work World Health Organization base benzimidazole benzimidazole resistance beta Tubulin disorder control egg exposed human population feeding field study global health health practice helminth infection high risk population in vitro Assay neglected tropical diseases prevent programs resistance allele resistance frequency response structural biology tool translational approach transmission process treatment response

项目摘要

Project Summary Hookworm infection is a leading cause of anemia and malnutrition in poor countries, especially in sub-Saharan Africa. The World Health Organization recommends repeated Mass Drug Administration of benzimidazole anthelminthics to high risk groups, including school age children, as a way to control morbidity and reduce transmission of hookworm and other Soil Transmitted Helminths. Although it is anticipated that hookworm resistance to benzimidazoles will eventually emerge, little is known about the frequency or distribution of resistant genotypes, as well as the potential for repeated anthelminthic exposure to reduce the effectiveness of deworming in human populations. Since 2007, the Ghana-Yale Partnership for Global Health has carried out collaborative field studies on hookworm epidemiology and deworming response, first in Kintampo North Municipality (KNM) and more recently Kpandai District (KD). Studies in adults and school age children (2007- 2015) have demonstrated reduced efficacy of albendazole, and preliminary data confirm the presence of putative benzimidazole resistance markers in N. americanus hookworms. We hypothesize that the mechanism of hookworm treatment failure in Kintampo involves genetically mediated resistance to albendazole. In Specific Aim 1, deworming effectiveness will be correlated with albendazole susceptibility using N. americanus isolates from KNM and KD in a field adapted in vitro assay. In Specific Aim 2, genomic DNA from hookworm field isolates will be used to define the temporal and spatial distribution of known benzimidazole resistance markers, as well as the genotypes associated with in vitro resistance and treatment failure. Studies in Specific Aim 3 will establish the structural basis of benzimidazole binding to hookworm β tubulin, as well as map the functional significance of putative resistance associated mutations. Finally, in Specific Aim 4 the effect of benzimidazole exposure on hookworm gene expression will be characterized using stage specific cultures of field adapted and laboratory strains of human parasites. In addition to creating new knowledge to promote Neglected Tropical Disease control, this project will provide a framework for ongoing collaborative research and training, building on the record of the Ghana-Yale Partnership for Global Health. Ultimately, development of molecular methods to elucidate the mechanisms of deworming treatment failure will bridge a pressing technological gap and fill a critical public health need in Ghana and other resource limited countries.

项目概要钩虫感染是贫穷国家（尤其是撒哈拉以南地区）贫血和营养不良的主要原因非洲。世界卫生组织建议重复实施苯并咪唑大规模药物管理。对高危人群（包括学龄儿童）使用驱虫药，作为控制发病率和减少发病率的一种方法钩虫和其他土壤传播的蠕虫的传播尽管预计钩虫会传播。对苯并咪唑的耐药性最终会出现，但人们对这种耐药性的频率或分布知之甚少。耐药基因型，以及反复接触驱虫药可能会降低其有效性自 2007 年以来，加纳-耶鲁全球健康伙伴关系开展了人类驱虫工作。关于钩虫流行病学和驱虫反应的合作实地研究，首先在金坦波北市政府 (KNM) 和最近的 Kpandai 区 (KD) 对成人和学龄儿童的研究（2007 年至今）。 2015）已证明阿苯达唑的功效降低，初步数据证实存在美洲钩虫中假定的苯并咪唑抗性标记我们寻找了该机制。 Kintampo 的钩虫治疗失败的原因与基因介导的阿苯达唑耐药性有关。目标 1，使用美洲猪笼草分离株的驱虫效果与阿苯达唑敏感性相关在特定目标 2 中，来自 KNM 和 KD 的现场适应体外测定，来自钩虫现场的基因组 DNA。分离株将用于定义已知苯并咪唑抗性标记物的时间和空间分布，以及与体外耐药性和治疗失败相关的基因型研究将在特定目标 3 中进行。建立苯并咪唑与钩虫β微管蛋白结合的结构基础，并绘制功能图谱最后，在具体目标 4 中，苯并咪唑的作用。钩虫基因表达的暴露将使用田间适应的阶段特定培养物来表征和人类寄生虫的实验室菌株除了创造新知识以促进被忽视的问题。热带疾病控制，该项目将为正在进行的合作研究和培训提供一个框架，最终，以加纳-耶鲁全球健康伙伴关系的记录为基础，开发分子技术。阐明驱虫治疗失败机制的方法将弥合紧迫的技术差距满足加纳和其他资源有限国家的关键公共卫生需求。