Translational studies of hookworm infection in Ghana

PROJECT SUMMARY
Hookworm infection is a leading cause of malnutrition and growth delay in poor countries, especially in sub-
Saharan Africa where millions of people are infected with Necator americanus. Data from human studies
suggest chronic hookworm infection also impairs routine vaccine efficacy and exacerbates other globally
important, co-endemic infectious diseases. Current strategies to control hookworm rely primarily on Mass Drug
Administration of standard anthelminthic drugs, although recent evidence calls into question the long-term
effectiveness of this approach to control and eliminate hookworm in endemic populations. Since 2007, Yale
University and the Noguchi Memorial Institute for Medical Research at the University of Ghana have
collaborated to characterize the epidemiology of hookworm infection in endemic communities. The longitudinal
field study proposed in Aim 1 will further probe the epidemiology of hookworm by defining risk factors for
infection, response to deworming, and reinfection following treatment in the Bono East Region, Ghana.
Experiments outlined in Aim 2 will be focused on characterizing changes in the frequency of resistance
associated mutations in the N. americanus β-tubulin gene using Next Generation Sequencing methods, as well
as the impact of drug pressure on genetic diversity and the population genetics of human hookworms in
Beposo. Critical to the detailed study of hookworm pathogenesis is the availability of a facile animal model that
is both reproducible and accurately reflects the major clinical features of human disease. Little is known about
N. americanus strains originating from populations in Africa, resulting in a significant gap in our understanding
of hookworm biology, genomics and evolution. Building on experience in maintaining the laboratory model of
Ancylostoma ceylanicum hookworms, field isolates of N. americanus cultured from study subjects in Ghana in
2019 have been used to establish patent infections in hamsters. In the experimental studies outlined in Aim 3,
clinical parameters and the kinetics of primary infection with the Ghana strain of N. americanus will be fully
characterized in the hamster model. Cellular, humoral and mucosal antibody responses to primary infection,
reinfection and vaccination with hookworm proteins will be defined. In addition, novel proteomic methods will be
applied to define human antibody profiles that correlate with infection status, intensity and risk of reinfection.
The overarching goals of the research outlined in this proposal are (1) to identify factors associated with
hookworm infection among people living in Beposo, Ghana, (2) to characterize the impact of deworming
pressure on drug resistance markers and genetic diversity of hookworms in Ghana and (3) to characterize the
first laboratory adapted African strain of N. americanus and optimize its utility for the study of human hookworm
epidemiology, pathogenesis and vaccine development. Results from these innovative studies will enhance our
understanding of hookworm pathogenesis in Africa and inform future development of public health tools to
reduce the global burden of this neglected tropical disease.

Grant Number: 3R01AI162826-05S1
NIH Institute/Center: NIH
Principal Investigator: MICHAEL CAPPELLO