Genomic approaches to define hookworm population diversity and deworming drug response

About This Grant

PROJECT SUMMARY Human hookworms infect approximately 500 million people worldwide and cause significant morbidity in women and children residing in the tropics. The WHO has set ambitious goals to eliminate hookworm infection as a public health problem by 2030. To meet these goals, mass drug administration (MDA) with benzimidazole anthelmintics (albendazole, mebendazole) has been scaled up in endemic areas. Concerningly some countries have reported reduced drug effectiveness, including Ghana. Although host factors may play a role, it remains to be determined if genetically mediated resistance to albendazole in hookworm populations is responsible for poor deworming drug response. The overall objective of this application is to address this knowledge gap by developing and applying hookworm genomic resources to field-based studies in Ghana in order to elucidate the role of hookworm (Necator americanus) genetics in albendazole treatment response. The central hypothesis of this proposal is that genomic differences in hookworm populations i) mediate parasite susceptibility to albendazole and ii) indicate barriers to cross-community transmission in Ghana. This hypothesis will be tested with three specific aims: 1) Create the first reference genome for N. americanus from Africa. The current reference genome for N. americanus, generated from an isogenic strain from China, is not representative of contemporary hookworm populations in Africa and falls short in the key quality metrics of contiguity and completeness. A laboratory strain of N. americanus recently adapted to the hamster model from hookworms in Ghana will be used to generate a complete, chromosome-scale reference genome. 2) Determine rates of gene flow between populations of N. americanus across Ghana. Epidemiological factors, including infection prevalence and cure rates, vary widely across Ghana; however, nothing is known about how hookworm populations across the country are connected. A cross-sectional survey of hookworm infection will be conducted in five communities spanning the width of Ghana, and whole genome sequencing will be utilized to determine connectivity between parasite populations. 3) Investigate the association between genomic differences and albendazole susceptibility in N. americanus from Ghana. Previous studies have identified communities in Kintampo North, Ghana, with variant responses to albendazole. Hookworm strains representing three variable treatment response phenotypes from these communities will be passaged in the animal model and screened for albendazole susceptibility, followed by a genome-wide association study to identify functional regions of the genome associated with drug susceptibility. The rationale for this project is that integrating hookworm genomics into MDA programs will offer a novel data stream to i) assess MDA effectiveness at the community level, ii) monitor for emerging anthelminthic resistance, and iii) improve our understanding of hookworm transmission dynamics. This research is significant because it represents the first comprehensive, multidisciplinary, genomics- based approach to investigate reduced deworming drug effectiveness for human hookworm infection in Africa.