Molecular Diagnostics and Epidemiology of Anthelmintic Efficacy in Hookworms and Whipworms
Creators: name: Venkatesan, Abhinaya
Publisher: name: Graduate Studies
Year: 2023
Subjects: subject: Drug resistance
subject: Ancylostoma
subject: Trichuris
subject: Amplicon sequencing
subject: Biology--Molecular
subject: Parasitology
subject: Bioinformatics
subject: FOS: Computer and information sciences

description: Broad-spectrum anthelmintics are widely used for treating parasitic nematode infections in humans and animals. The frequent and extensive use of these drugs has resulted in widespread anthelmintic resistance in nematodes of livestock, which is increasingly well documented. In contrast, while anecdotal and clinical data often suggest poor efficacy, the extent and molecular basis of anthelmintic resistance in parasitic nematodes of humans and companion animals is still poorly understood. This thesis uses molecular genetic approaches to investigate two significant and contemporary examples of poor anthelmintic efficacy in parasitic nematodes. Firstly, a parasite of dogs, Ancylostoma caninum, for which there have been many clinical and anecdotal reports of poor efficacy for multiple drug classes for some time. Secondly, an important parasite of humans, Trichuris trichiura, where a population which is refractory to albendazole-ivermectin combination therapy has recently been identified. Ancylostoma caninum (canine hookworm) is an important gastrointestinal parasitic nematode of dogs. The parasite prevalence in the USA has seen a dramatic increase in the past decade with anecdotal reports of reduced drug efficacy and suspected cases of anthelmintic resistance. Chapter 2 of the thesis identifies and functionally characterizes a novel benzimidazole resistance mutation at codon 134 of the A. caninum isotype-1 β-tubulin gene. A deep amplicon sequencing approach was utilized for the large-scale screening of this novel and other previously described benzimidazole resistance mutations, revealing that benzimidazole resistance is now widespread in A. caninum from pet dogs across the USA. Chapter 3 examines the molecular epidemiology of the benzimidazole resistance alleles and the genetic diversity of A. caninum in pet dogs to investigate the emergence and spread of anthelmintic resistance in the parasite populations. The results support the hypothesis that at least some benzimidazole resistance alleles originated in racing greyhound kennels due to intense drug selection pressure and subsequently spread into pet dog populations via the rehoming of retired racing greyhounds. Chapter 4 focuses on the second parasitic nematode, Trichuris trichiura (human whipworm). This soil transmitted helminth (STH) species of global health importance has been particularly problematic due to its poor sensitivity to benzimidazoles, which are widely administered anthelmintics in Mass Drug Administration (MDA) programs. This thesis chapter investigates genetic differences in Trichuris populations from clinical efficacy trials in three different countries: Côte d’Ivoire, Lao PDR, and Tanzania. Genetic analysis suggests that the parasite populations in Côte d’Ivoire, which is non-responsive to albendazole-ivermectin treatment, is a separate Trichuris species, distinct from T. trichiura. The results from this thesis illustrate the power of molecular genetic approaches to elucidate the basis of poor anthelmintic efficacy and provide a framework for molecular epidemiology and surveillance studies.