The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF‑12.
Résumé
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. Nuclear receptors (NRs) are transcription factors involved in key physiological processes such as growth and development, aging and reproduction, as well as metabolism and detoxification of endo-and xenobiotics 1-4. They typically bind small lipophilic molecules, resulting in their activation, which allows the receptor to recruit co-regulators of expression of specific genes 5. Because of their central role in critical metabolic processes, including development, NRs are relevant targets for drug discovery 2. It is estimated that 10-20% of the pharmaceutical market targets these receptors in humans 5. NRs are conserved among metazoans including helminths 6. While humans harbor 49 NRs in their genome, Caenorhabditis elegans has 284 NRs 7 and some are essential for development and reproduction but also survival by enabling this free-living worm to adapt to variable environmental conditions. DAF-12 was described as a NR in C. elegans, due to the discovery of its ligands, dafachronic acids (Δ4-and Δ7-DA) 8-10. In this nematode, DAF-12 acts as a molecular switch in the signaling pathway that regulates dauer formation, or alternative progression to reproductive development and the adult stage, by sensing the environmental quality and bacterial nutrient availability 9,11. When environmental conditions are favorable, and bacteria are available, C. elegans stimulates the production of DA steroid hormones, which activate DAF-12 7,10,12. CelDAF-12 then induces transcription of development genes that promote growth and reproduction 13-15. In contrast, in unfavorable conditions, DAs are not synthesized and the DAF-12 apo-receptor interacts with a co-repressor, preventing target gene expression and resulting in arrest of development at dauer diapause larvae, a non-feeding, non-reproducing, stress-resistant, open
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