Phenotypic and molecular analysis of the effect of 20-hydroxyecdysone on the human filarial parasite Brugia malayi

Mhashilkar, Amruta S.; Adapa, Swamy Rakesh; Jiang, Rays H. Y.; Williams, Steven A.; Zaky, Weam I.; Slatko, Barton E.; Luck, Ashley N.; Moorhead, Andrew R.; Unnasch, Thomas R.

doi:10.1016/j.ijpara.2016.01.005

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…In comparison to C. elegans and B. malayi , the NHR repertoire is smaller in O. volvulus (9) but still contains all five NHR genes that play a role in molting and embryogenesis (28, 29). Indeed, the O. volvulus ecdysone receptor (EcR, OVOC9104) and NHR RXR (OVOC2435) show increased expression during the L3-to-L4 molt (https://exon.niaid.nih.gov/transcriptome/O_volvulus/Additional_file_11.tif).…”

Section: Resultsmentioning

confidence: 99%

Stage-Specific Transcriptome and Proteome Analyses of the Filarial Parasite Onchocerca volvulus and Its Wolbachia Endosymbiont

Bennuru

Cotton

Ribeiro

et al. 2016

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Onchocerciasis (river blindness) is a neglected tropical disease that has been successfully targeted by mass drug treatment programs in the Americas and small parts of Africa. Achieving the long-term goal of elimination of onchocerciasis, however, requires additional tools, including drugs, vaccines, and biomarkers of infection. Here, we describe the transcriptome and proteome profiles of the major vector and the human host stages (L1, L2, L3, molting L3, L4, adult male, and adult female) of Onchocerca volvulus along with the proteome of each parasitic stage and of its Wolbachia endosymbiont (wOv). In so doing, we have identified stage-specific pathways important to the parasite’s adaptation to its human host during its early development. Further, we generated a protein array that, when screened with well-characterized human samples, identified novel diagnostic biomarkers of O. volvulus infection and new potential vaccine candidates. This immunomic approach not only demonstrates the power of this postgenomic discovery platform but also provides additional tools for onchocerciasis control programs.

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Section: Resultsmentioning

confidence: 99%

Stage-Specific Transcriptome and Proteome Analyses of the Filarial Parasite Onchocerca volvulus and Its Wolbachia Endosymbiont

Bennuru

Cotton

Ribeiro

et al. 2016

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“…Previous studies have demonstrated that 20E stimulated expulsion of immature progeny (eggs, embryos and immature microfilariae) from adult female parasites cultured in the presence of 20E [ 45 ]. However, by analogy to its role in insects, the Bma EcR could be hypothesized to play an important role in molting in the filarial parasites as well.…”

Section: Resultsmentioning

confidence: 99%

“…In keeping with this expression pattern, recent studies have demonstrated that 20E affected egg development and embryognesis in adult female B . malayi [ 45 ]. The data presented above, though limited, suggests that 20E also interferes with the development of infective larvae to adult parasites, a process involving two molts.…”

Section: Discussionmentioning

confidence: 99%

Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections

et al. 2016

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BackgroundA homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets.Methodology/ Principal FindingsAdministration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites.ConclusionsThe studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites.

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“…While some of the motifs we identified are conserved in other nematodes, such as C. elegans , a number of motifs represent novel binding sites potentially reflecting the differences in development and the parasitic lifestyle. It is known that molting is regulated by an ecdysone-like response system (Barker et al 1991; Mhashilkar at al. 2016; Mhashilkar at al.…”

Section: Discussionmentioning

confidence: 99%

Prediction pipeline for discovery of regulatory motifs associated with Brugia malayi molting

Grote

Liu

et al. 2019

Preprint

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25Filarial nematodes can cause debilitating diseases in humans. They have complicated 26 life cycles involving an insect vector and mammalian hosts, and they go through a 27 number of developmental molts. While whole genome sequences of parasitic worms are 28 now available, very little is known about transcription factor (TF) binding sites and their 29 cognate transcription factors that play a role in regulating development. To address this 30 gap, we developed a novel motif prediction pipeline, Emotif Alpha, that integrates ten 31 different motif discovery algorithms, multiple statistical tests, and a comparative analysis 32 of conserved elements between the filarial worms Brugia malayi and Onchocerca 33 volvulus, and the free-living nematode Caenorhabditis elegans. We identified stage-34 specific TF binding motifs in B. malayi, with a particular focus on those potentially 35 involved in the L3-L4 molt, a stage important for the establishment of infection in the 36 mammalian host. Using an in vitro molting system, we tested and validated three of 37

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Phenotypic and molecular analysis of the effect of 20-hydroxyecdysone on the human filarial parasite Brugia malayi

Cited by 12 publications

References 38 publications

Stage-Specific Transcriptome and Proteome Analyses of the Filarial Parasite Onchocerca volvulus and Its Wolbachia Endosymbiont

Stage-Specific Transcriptome and Proteome Analyses of the Filarial Parasite Onchocerca volvulus and Its Wolbachia Endosymbiont

Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections

Prediction pipeline for discovery of regulatory motifs associated with Brugia malayi molting

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