Emerging benzimidazole resistance in human hookworms

人类钩虫中出现的苯并咪唑耐药性

• 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
• 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

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。 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.尽管预计钩虫 resistance to benzimidazoles will eventually emerge, little is known about the frequency or distribution of 耐药基因型，以及反复接触驱虫药可能会降低其有效性 对人群进行驱虫。 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).针对成人和学龄儿童的研究（2007- 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。我们假设该机制 金坦波的钩虫治疗失败的一个原因是基因介导的对阿苯达唑的耐药性。具体来说 目标 1，使用美洲奈瑟菌分离株的驱虫效果与阿苯达唑敏感性相关 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.具体目标 3 的研究将 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 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 和人类寄生虫的实验室菌株。除了创造新知识来促进被忽视的 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.最终，分子技术的发展 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。