Emerging benzimidazole resistance in human hookworms

人类钩虫中出现的苯并咪唑耐药性

• 批准号: 10159191
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159191
• 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。世界卫生组织建议重复进行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 钩虫和其他土传蠕虫的传播。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 对人群进行驱虫。自 2007 年以来，加纳-耶鲁全球健康伙伴关系开展了 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)。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 来自 KNM 和 KD 在现场适应的体外测定中。在具体目标 2 中，来自钩虫领域的基因组 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。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 假定的耐药性相关突变的重要性。最后，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。除了创造新知识来促进被忽视的 热带病控制，该项目将为正在进行的合作研究和培训提供一个框架， 以加纳-耶鲁全球健康伙伴关系的记录为基础。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。

项目成果

Plasmodium falciparum coinfection is associated with improved IgE and IgG3 response against hookworm antigens.

• DOI: 10.1002/hsr2.672
• 发表时间: 2022-07
• 期刊: HEALTH SCIENCE REPORTS
• 影响因子: 2
• 作者: Sakyi, Samuel A.;Wilson, Michael D.;Adu, Bright;Opoku, Stephen;Brewoo, Antwi;Larbi, Amma;Baafour, Emmanuel K.;Tchum, Samuel K.;Saahene, Roland O.;Aniagyei, Wilfred;Sewor, Christian;Courtin, David;Cappello, Michael;Gyan, Ben;Amoani, Benjamin
• 通讯作者: Amoani, Benjamin

Application of multiplex amplicon deep-sequencing (MAD-seq) to screen for putative drug resistance markers in the Necator americanus isotype-1 β-tubulin gene.

• DOI: 10.1038/s41598-022-15718-1
• 发表时间: 2022-07-06
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: George, Santosh;Suwondo, Peter;Akorli, Jewelna;Otchere, Joseph;Harrison, Lisa M.;Bilguvar, Kaya;Knight, James R.;Humphries, Debbie;Wilson, Michael D.;Caccone, Adalgisa;Cappello, Michael
• 通讯作者: Cappello, Michael

Comparison of percutaneous vs oral infection of hamsters with the hookworm Ancylostoma ceylanicum: Parasite development, pathology and primary immune response.

• DOI: 10.1371/journal.pntd.0010098
• 发表时间: 2022-01
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Bungiro RD;Harrison LM;Dondji B;Cappello M
• 通讯作者: Cappello M