Emerging benzimidazole resistance in human hookworms

项目摘要 钩虫感染是贫穷国家，特别是撒哈拉以南非洲国家贫血和营养不良的主要原因 非洲世界卫生组织建议重复大规模药物管理的苯并咪唑 向包括学龄儿童在内的高风险群体提供驱虫药，作为控制发病率和减少 钩虫和其他土壤传播蠕虫的传播。尽管预计钩虫 对苯并咪唑的耐药性最终会出现，但对苯并咪唑的频率或分布知之甚少。 耐药基因型，以及重复驱虫剂暴露的可能性，以降低有效性 对人群进行驱虫。自2007年以来，加纳-耶鲁全球卫生伙伴关系开展了 关于钩虫流行病学和驱虫对策的合作实地研究，首先在北金丹波进行 市（KNM）和最近Kpandai区（KD）。对成人和学龄儿童的研究（2007- 2015）已经证明阿苯达唑的疗效降低，初步数据证实存在 在N.美洲钩虫我们假设 金坦波钩虫治疗失败的原因是基因介导的阿苯达唑耐药性。在特定 目的1.用N.美洲分离物 来自KNM和KD的现场适应性体外试验。在特定目标2中，来自钩虫领域的基因组DNA 分离物将用于确定已知苯并咪唑抗性标记的时间和空间分布， 以及与体外抗性和治疗失败相关的基因型。具体目标3的研究将 建立了苯并咪唑与钩虫β微管蛋白结合的结构基础，并绘制了其功能图谱。 推定的耐药相关突变的意义。最后，在具体目标4中， 暴露对钩虫基因表达的影响将使用田间适应的阶段特异性培养物进行表征。 和实验室里的人类寄生虫除了创造新知识以促进被忽视的 热带疾病控制，这一项目将为正在进行的合作研究和培训提供一个框架， 建立在加纳-耶鲁全球健康伙伴关系的基础上。最终，分子的发展 阐明驱虫治疗失败机制的方法将弥合一个紧迫的技术差距， 并满足加纳和其他资源有限国家的关键公共卫生需求。

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.