Emerging benzimidazole resistance in human hookworms

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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.