De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells.
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 pa...
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Series: | PLoS Neglected Tropical Diseases |
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doaj-333b6dc197914f47b2c753a9dd44b1bc2021-03-03T07:56:14ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352020-05-01145e000794210.1371/journal.pntd.0007942De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells.Douglas P JasmerBruce A RosaRahul TyagiChristina A BulmanBrenda BeerntsenJoseph F UrbanJudy SakanariMakedonka MitrevaEfforts 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.https://doi.org/10.1371/journal.pntd.0007942 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Douglas P Jasmer Bruce A Rosa Rahul Tyagi Christina A Bulman Brenda Beerntsen Joseph F Urban Judy Sakanari Makedonka Mitreva |
spellingShingle |
Douglas P Jasmer Bruce A Rosa Rahul Tyagi Christina A Bulman Brenda Beerntsen Joseph F Urban Judy Sakanari Makedonka Mitreva De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells. PLoS Neglected Tropical Diseases |
author_facet |
Douglas P Jasmer Bruce A Rosa Rahul Tyagi Christina A Bulman Brenda Beerntsen Joseph F Urban Judy Sakanari Makedonka Mitreva |
author_sort |
Douglas P Jasmer |
title |
De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells. |
title_short |
De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells. |
title_full |
De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells. |
title_fullStr |
De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells. |
title_full_unstemmed |
De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells. |
title_sort |
de novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Neglected Tropical Diseases |
issn |
1935-2727 1935-2735 |
publishDate |
2020-05-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.pntd.0007942 |
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