The Effects of Ivermectin on Brugia malayi Females In Vitro: A Transcriptomic Approach.
BACKGROUND:Lymphatic filariasis and onchocerciasis are disabling and disfiguring neglected tropical diseases of major importance in developing countries. Ivermectin is the drug of choice for mass drug administration programs for the control of onchocerciasis and lymphatic filariasis in areas where t...
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ftdoajarticles:oai:doaj.org/article:d3b53452fdca4f4d9f24ce3a220ad952 2023-05-15T15:13:52+02:00 The Effects of Ivermectin on Brugia malayi Females In Vitro: A Transcriptomic Approach. Cristina Ballesteros Lucienne Tritten Maeghan O'Neill Erica Burkman Weam I Zaky Jianguo Xia Andrew Moorhead Steven A Williams Timothy G Geary 2016-08-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004929 https://doaj.org/article/d3b53452fdca4f4d9f24ce3a220ad952 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4986938?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004929 https://doaj.org/article/d3b53452fdca4f4d9f24ce3a220ad952 PLoS Neglected Tropical Diseases, Vol 10, Iss 8, p e0004929 (2016) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2016 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004929 2022-12-31T03:20:05Z BACKGROUND:Lymphatic filariasis and onchocerciasis are disabling and disfiguring neglected tropical diseases of major importance in developing countries. Ivermectin is the drug of choice for mass drug administration programs for the control of onchocerciasis and lymphatic filariasis in areas where the diseases are co-endemic. Although ivermectin paralyzes somatic and pharyngeal muscles in many nematodes, these actions are poorly characterized in adult filariae. We hypothesize that paralysis of pharyngeal pumping by ivermectin in filariae could result in deprivation of essential nutrients, especially iron, inducing a wide range of responses evidenced by altered gene expression, changes in metabolic pathways, and altered developmental states in embryos. Previous studies have shown that ivermectin treatment significantly reduces microfilariae release from females within four days of exposure in vivo, while not markedly affecting adult worms. However, the mechanisms responsible for reduced production of microfilariae are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS:We analyzed transcriptomic profiles from Brugia malayi adult females, an important model for other filariae, using RNAseq technology after exposure in culture to ivermectin at various concentrations (100 nM, 300 nM and 1 μM) and time points (24, 48, 72 h, and 5 days). Our analysis revealed drug-related changes in expression of genes involved in meiosis, as well as oxidative phosphorylation, which were significantly down-regulated as early as 24 h post-exposure. RNA interference phenotypes of the orthologs of these down-regulated genes in C. elegans include "maternal sterile", "embryonic lethal", "larval arrest", "larval lethal" and "sick". CONCLUSION/SIGNIFICANCE:These changes provide insight into the mechanisms involved in ivermectin-induced reduction in microfilaria output and impaired fertility, embryogenesis, and larval development. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 10 8 e0004929 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Cristina Ballesteros Lucienne Tritten Maeghan O'Neill Erica Burkman Weam I Zaky Jianguo Xia Andrew Moorhead Steven A Williams Timothy G Geary The Effects of Ivermectin on Brugia malayi Females In Vitro: A Transcriptomic Approach. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
BACKGROUND:Lymphatic filariasis and onchocerciasis are disabling and disfiguring neglected tropical diseases of major importance in developing countries. Ivermectin is the drug of choice for mass drug administration programs for the control of onchocerciasis and lymphatic filariasis in areas where the diseases are co-endemic. Although ivermectin paralyzes somatic and pharyngeal muscles in many nematodes, these actions are poorly characterized in adult filariae. We hypothesize that paralysis of pharyngeal pumping by ivermectin in filariae could result in deprivation of essential nutrients, especially iron, inducing a wide range of responses evidenced by altered gene expression, changes in metabolic pathways, and altered developmental states in embryos. Previous studies have shown that ivermectin treatment significantly reduces microfilariae release from females within four days of exposure in vivo, while not markedly affecting adult worms. However, the mechanisms responsible for reduced production of microfilariae are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS:We analyzed transcriptomic profiles from Brugia malayi adult females, an important model for other filariae, using RNAseq technology after exposure in culture to ivermectin at various concentrations (100 nM, 300 nM and 1 μM) and time points (24, 48, 72 h, and 5 days). Our analysis revealed drug-related changes in expression of genes involved in meiosis, as well as oxidative phosphorylation, which were significantly down-regulated as early as 24 h post-exposure. RNA interference phenotypes of the orthologs of these down-regulated genes in C. elegans include "maternal sterile", "embryonic lethal", "larval arrest", "larval lethal" and "sick". CONCLUSION/SIGNIFICANCE:These changes provide insight into the mechanisms involved in ivermectin-induced reduction in microfilaria output and impaired fertility, embryogenesis, and larval development. |
format |
Article in Journal/Newspaper |
author |
Cristina Ballesteros Lucienne Tritten Maeghan O'Neill Erica Burkman Weam I Zaky Jianguo Xia Andrew Moorhead Steven A Williams Timothy G Geary |
author_facet |
Cristina Ballesteros Lucienne Tritten Maeghan O'Neill Erica Burkman Weam I Zaky Jianguo Xia Andrew Moorhead Steven A Williams Timothy G Geary |
author_sort |
Cristina Ballesteros |
title |
The Effects of Ivermectin on Brugia malayi Females In Vitro: A Transcriptomic Approach. |
title_short |
The Effects of Ivermectin on Brugia malayi Females In Vitro: A Transcriptomic Approach. |
title_full |
The Effects of Ivermectin on Brugia malayi Females In Vitro: A Transcriptomic Approach. |
title_fullStr |
The Effects of Ivermectin on Brugia malayi Females In Vitro: A Transcriptomic Approach. |
title_full_unstemmed |
The Effects of Ivermectin on Brugia malayi Females In Vitro: A Transcriptomic Approach. |
title_sort |
effects of ivermectin on brugia malayi females in vitro: a transcriptomic approach. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2016 |
url |
https://doi.org/10.1371/journal.pntd.0004929 https://doaj.org/article/d3b53452fdca4f4d9f24ce3a220ad952 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 10, Iss 8, p e0004929 (2016) |
op_relation |
http://europepmc.org/articles/PMC4986938?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004929 https://doaj.org/article/d3b53452fdca4f4d9f24ce3a220ad952 |
op_doi |
https://doi.org/10.1371/journal.pntd.0004929 |
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PLOS Neglected Tropical Diseases |
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10 |
container_issue |
8 |
container_start_page |
e0004929 |
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