Date of Award
8-7-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Gastrointestinal nematodes (GINs) collectively infect 1.5 billion people, leading to mortality and various forms of morbidity in humans and hindering normal development in children. GINs also diminish the productivity of food animals, which are crucial for economic and nutritional well-being, particularly in developing countries. Currently, the world still primarily relies on only a few drug classes for global de-worming of GINs in humans and animals. However, the high rate of reinfection, disappointing treatment success rates, and increasing drug resistance make GINs one of the most important contributors to promoting and maintaining global poverty. This highlights the urgent need for more effective anthelmintic drugs with novel modes of action and broad-spectrum activity against multiple parasitic nematodes due to frequent concomitant infections and the impracticality of treating each parasite individually during mass deworming. The biological and genomic complexity of nematodes has hindered the identification of principles that could universally advance parasite control. To address these challenges, this dissertation hypothesizes that conserved anthelmintic targets can be identified by focusing on a group of closely related parasitic nematodes defined by their taxonomic, phylogenetic, and/or evolutionary relationships, which often lead to similar preferences and habitats within their hosts. Thus, by interrogating multi-omics data and evolutionary principles, this dissertation aims to identify conserved molecular targets in the early parasitic stages of GINs, providing a foundation for the development of more effective interventions. The focus is on early parasitic stages so that the lifecycle of the nematodes can be disrupted, preventing them from reaching maturity and reproducing, which could significantly reduce the population of the parasites and the likelihood of reinfection. Chapter 2 focuses on identifying conserved drug targets among ruminant GINs and prioritizing compounds with anthelmintic potential targeting the early parasitic stages. In vitro screening of prioritized drugs (having chemical properties frequently found in successful drugs) against exsheathed L3 larvae (mimicking the first parasitic stage following the ingestion of free-living sheathed L3 by their hosts) of three different GIN species confirmed that majority of our predictions are correct and identified drugs having anthelmintics activities in all 3 species. These results have potential to expedite the discovery of new anthelmintic drugs with broad-spectrum efficacy against ruminant GINs. Building on this approach, Chapter 3 investigates the early stage of whipworm infection (human and murine) and prioritizes molecular targets likely playing crucial roles in penetrating the intestinal mucosa and establishing infection in the intestinal habitats. Due to the intracellular nature of L1 whipworm, which affects a small portion of epithelial cells and resides at the bottom of the intestinal epithelium, studying them in vivo has been challenging. Therefore, mouse colonoids were established and evaluated as an in vitro model system by characterizing and comparing their transcriptomic profiles to in vivo early whipworm infection. Integrative omics analysis, including new transcriptomic data generated from this dissertation, led to much better understanding of the host intestinal response to early whipworm infection and the identification of candidate mucus-degrading enzymes, with ongoing efforts to evaluate their enzymatic activities and characterize their role in the early infection. Overall, this dissertation demonstrates how leveraging multi-omics data, evolutionary principles and advanced animal models can lead to the identification of conserved anthelmintic targets in the early parasitic stages of gastrointestinal nematodes. These findings provide a promising foundation for future studies aimed at developing therapeutics that target these early stages of GIN development.
Language
English (en)
Chair and Committee
Makedonka Mitreva
Committee Members
James Fleckenstein; James Janetka; Peter Fischer; Phillip Tarr
Recommended Citation
Jung, Hyeim, "Discovering and Characterizing Conserved Anthelmintic Targets in the Early Parasitic Stages of Gastrointestinal Nematodes" (2024). Arts & Sciences Electronic Theses and Dissertations. 3301.
https://openscholarship.wustl.edu/art_sci_etds/3301