Investigating the genetics and genomics of antiparasitic drug responses in a poultry model of ascariasis

PROJECT SUMMARY
Infections with the parasitic nematode Ascaris lumbricoides affect up to an estimated 1.2 billion people
worldwide, causing significant disease and accounting for the loss of 749,000 Disability Adjusted Life Years
(DALYs) annually. Treatment of these infections in most endemic regions depends on mass drug administration
(MDA) programs primarily comprising benzimidazoles (BZ), such as albendazole and mebendazole.
Large-scale and prolonged usage of BZs selects for resistance in parasitic nematodes, as observed in
veterinary parasites (e.g., Haemonchus contortus, a parasite of small ruminants). Although no confirmed cases
of BZ resistance in human ascariasis have been described, BZ resistance has been confirmed in ascarids of
veterinary importance. Importantly, these veterinary parasites also appear to lack canonical alleles associated
with BZ resistance in other parasite species, suggesting that resistance mechanisms in ascarids likely differ.
Everything currently known about BZ resistance comes from studies of the model nematode Caenorhabditis
elegans and closely related parasites such as H. contortus. However, 350 million years of evolution separate
C. elegans and ascarids, limiting its use as a model for ascarid research. Therefore, it is necessary to establish
a new, more closely related, model to study BZ resistance in ascarids. Ascaridia dissimilis offers a powerful
model system to study BZ resistance in human ascarids because established resistant and susceptible isolates
exist, labor costs are lower than other veterinary parasites, and importantly no human infections are required.
Human parasites cannot be readily studied because of the ethical issues associated with controlled infections,
as well as difficulties in manipulating such a model. This project will identify genetic variants associated with BZ
resistance in ascarids, using poultry ascarids as a new model system, allowing for diagnostics to be developed
and improving treatment programs to control human infections. Aim 1 will create high-quality reference
genomes for sensitive and resistant A. dissimilis isolates. Reference genomes will allow known resistance
associated genes to be analyzed for high-impact variants, and enable future studies, including genome-wide
mapping. Aim 2 will use genetic crosses and BZ selection to create recombinant isolates with BZ resistance
associated loci in an otherwise susceptible background. After initial crossing of the resistant and susceptible
isolates, progeny will be backcrossed with the susceptible parental line and selected for BZ resistance and
used in a bulk-segregant analysis approach to identify BZ resistance loci. This innovative poultry ascarid
system enables discoveries of conserved BZ resistance loci in a tractable model. Results can then be
translated to human ascarids to improve the quality of care and quality of life for infected individuals across the
developing world.

Grant Number: 5R21AI180805-02
NIH Institute/Center: NIH
Principal Investigator: Erik Andersen