The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12

Abstract Prevention therapy against Dirofilaria immitis in companion animals is currently threatened by the emergence of isolates resistant to macrocyclic lactone anthelmintics. Understanding the control over developmental processes in D. immitis is important for elucidating new approaches to heartw...

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Autores principales:	Thavy Long, Mélanie Alberich, François André, Cécile Menez, Roger K. Prichard, Anne Lespine
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/108c836ccade4cb094a7790f86b21298
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spelling	oai:doaj.org-article:108c836ccade4cb094a7790f86b212982021-12-02T15:39:49ZThe development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-1210.1038/s41598-020-67466-92045-2322https://doaj.org/article/108c836ccade4cb094a7790f86b212982020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-67466-9https://doaj.org/toc/2045-2322Abstract Prevention therapy against Dirofilaria immitis in companion animals is currently threatened by the emergence of isolates resistant to macrocyclic lactone anthelmintics. Understanding the control over developmental processes in D. immitis is important for elucidating new approaches to heartworm control. The nuclear receptor DAF-12 plays a role in the entry and exit of dauer stage in Caenorhabditis elegans and in the development of free-living infective third-stage larvae (iL3) of some Clade IV and V parasitic nematodes. We identified a DAF-12 ortholog in the clade III nematode D. immitis and found that it exhibited a much higher affinity for dafachronic acids than described with other nematode DAF-12 investigated so far. We also modelled the DimDAF-12 structure and characterized the residues involved with DA binding. Moreover, we showed that cholesterol derivatives impacted the molting process from the iL3 to the fourth-stage larvae. Since D. immitis is unable to synthesize cholesterol and only completes its development upon host infection, we hypothesize that host environment contributes to its further molting inside the host vertebrate. Our discovery contributes to a better understanding of the developmental checkpoints of D. immitis and offers new perspectives for the development of novel therapies against filarial infections.Thavy LongMélanie AlberichFrançois AndréCécile MenezRoger K. PrichardAnne LespineNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thavy Long Mélanie Alberich François André Cécile Menez Roger K. Prichard Anne Lespine The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12
description	Abstract Prevention therapy against Dirofilaria immitis in companion animals is currently threatened by the emergence of isolates resistant to macrocyclic lactone anthelmintics. Understanding the control over developmental processes in D. immitis is important for elucidating new approaches to heartworm control. The nuclear receptor DAF-12 plays a role in the entry and exit of dauer stage in Caenorhabditis elegans and in the development of free-living infective third-stage larvae (iL3) of some Clade IV and V parasitic nematodes. We identified a DAF-12 ortholog in the clade III nematode D. immitis and found that it exhibited a much higher affinity for dafachronic acids than described with other nematode DAF-12 investigated so far. We also modelled the DimDAF-12 structure and characterized the residues involved with DA binding. Moreover, we showed that cholesterol derivatives impacted the molting process from the iL3 to the fourth-stage larvae. Since D. immitis is unable to synthesize cholesterol and only completes its development upon host infection, we hypothesize that host environment contributes to its further molting inside the host vertebrate. Our discovery contributes to a better understanding of the developmental checkpoints of D. immitis and offers new perspectives for the development of novel therapies against filarial infections.
format	article
author	Thavy Long Mélanie Alberich François André Cécile Menez Roger K. Prichard Anne Lespine
author_facet	Thavy Long Mélanie Alberich François André Cécile Menez Roger K. Prichard Anne Lespine
author_sort	Thavy Long
title	The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12
title_short	The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12
title_full	The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12
title_fullStr	The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12
title_full_unstemmed	The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12
title_sort	development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor daf-12
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/108c836ccade4cb094a7790f86b21298
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The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12

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