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.