2. Academic Validation
  3. De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells

De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells

  • PLoS Negl Trop Dis. 2020 May 26;14(5):e0007942. doi: 10.1371/journal.pntd.0007942.
Douglas P Jasmer 1,  Bruce A Rosa 2,  Rahul Tyagi 3,  Christina A Bulman 4,  Brenda Beerntsen 5,  Joseph F Urban Jr 6,  Judy Sakanari 4,  Makedonka Mitreva 2 3
Affiliations

Affiliations

  • 1 Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington, United States of America.
  • 2 Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
  • 3 McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
  • 4 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America.
  • 5 Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, United States of America.
  • 6 U.S. Department of Agriculture, Northeast Area, Agricultural Research Service, Beltsville Agricultural Research Center, Animal Parasite Diseases Laboratory and Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, Maryland, United States of America.
PMID: 32453724 DOI: 10.1371/journal.pntd.0007942
Abstract

Efforts to identify new drugs for therapeutic and preventive treatments against parasitic nematodes have gained increasing interest with expanding pathogen omics databases and drug databases from which new anthelmintic compounds might be identified. Here, a novel approach focused on integrating a pan-Nematoda multi-omics data targeted to a specific nematode organ system (the intestinal tract) with evidence-based filtering and chemogenomic screening was undertaken. Based on de novo computational target prioritization of the 3,564 conserved intestine genes in A. suum, exocytosis was identified as a high priority pathway, and predicted inhibitors of exocytosis were tested using the large roundworm (Ascaris suum larval stages), a filarial worm (Brugia pahangi adult and L3), a whipworm (Trichuris muris adult), and the non-parasitic nematode Caenorhabditis elegans. 10 of 13 inhibitors were found to cause rapid immotility in A. suum L3 larvae, and five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Several distinct pathologic phenotypes were resolved related to molting, motility, or intestinal cell and tissue damage using conventional and novel histologic methods. Pathologic profiles characteristic for each inhibitor will guide future research to uncover mechanisms of the anthelmintic effects and improve on drug designs. This progress firmly validates the focus on intestinal Cell Biology as a useful resource to develop novel anthelmintic strategies.

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