Drug Repurposing of Bromodomain Inhibitors as Potential Novel Therapeutic Leads for Lymphatic Filariasis Guided by Multispecies Transcriptomics

ABSTRACT To better understand the transcriptomic interplay of organisms associated with lymphatic filariasis, we conducted multispecies transcriptome sequencing (RNA-Seq) on the filarial nematode Brugia malayi, its Wolbachia endosymbiont wBm, and its laboratory vector Aedes aegypti across the entire...

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Autores principales:	Matthew Chung, Laura E. Teigen, Silvia Libro, Robin E. Bromley, Dustin Olley, Nikhil Kumar, Lisa Sadzewicz, Luke J. Tallon, Anup Mahurkar, Jeremy M. Foster, Michelle L. Michalski, Julie C. Dunning Hotopp
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	lymphatic filariasis filarial nematodes nematodes Brugia malayi Wolbachia Aedes aegypti Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1e447a65c7f547f7b29505baa9201b24
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spelling	oai:doaj.org-article:1e447a65c7f547f7b29505baa9201b242021-12-02T18:15:44ZDrug Repurposing of Bromodomain Inhibitors as Potential Novel Therapeutic Leads for Lymphatic Filariasis Guided by Multispecies Transcriptomics10.1128/mSystems.00596-192379-5077https://doaj.org/article/1e447a65c7f547f7b29505baa9201b242019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00596-19https://doaj.org/toc/2379-5077ABSTRACT To better understand the transcriptomic interplay of organisms associated with lymphatic filariasis, we conducted multispecies transcriptome sequencing (RNA-Seq) on the filarial nematode Brugia malayi, its Wolbachia endosymbiont wBm, and its laboratory vector Aedes aegypti across the entire B. malayi life cycle. In wBm, transcription of the noncoding 6S RNA suggests that it may be a regulator of bacterial cell growth, as its transcript levels correlate with bacterial replication rates. For A. aegypti, the transcriptional response reflects the stress that B. malayi infection exerts on the mosquito with indicators of increased energy demand. In B. malayi, expression modules associated with adult female samples consistently contained an overrepresentation of genes involved in chromatin remodeling, such as the bromodomain-containing proteins. All bromodomain-containing proteins encoded by B. malayi were observed to be upregulated in the adult female, embryo, and microfilaria life stages, including 2 members of the bromodomain and extraterminal (BET) protein family. The BET inhibitor JQ1(+), originally developed as a cancer therapeutic, caused lethality of adult worms in vitro, suggesting that it may be a potential therapeutic that can be repurposed for treating lymphatic filariasis. IMPORTANCE The current treatment regimen for lymphatic filariasis is mostly microfilaricidal. In an effort to identify new drug candidates for lymphatic filariasis, we conducted a three-way transcriptomics/systems biology study of one of the causative agents of lymphatic filariasis, Brugia malayi, its Wolbachia endosymbiont wBm, and its vector host Aedes aegypti at 16 distinct B. malayi life stages. B. malayi upregulates the expression of bromodomain-containing proteins in the adult female, embryo, and microfilaria stages. In vitro, we find that the existing cancer therapeutic JQ1(+), which is a bromodomain and extraterminal protein inhibitor, has adulticidal activity in B. malayi.Matthew ChungLaura E. TeigenSilvia LibroRobin E. BromleyDustin OlleyNikhil KumarLisa SadzewiczLuke J. TallonAnup MahurkarJeremy M. FosterMichelle L. MichalskiJulie C. Dunning HotoppAmerican Society for Microbiologyarticlelymphatic filariasisfilarial nematodesnematodesBrugia malayiWolbachiaAedes aegyptiMicrobiologyQR1-502ENmSystems, Vol 4, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	lymphatic filariasis filarial nematodes nematodes Brugia malayi Wolbachia Aedes aegypti Microbiology QR1-502
spellingShingle	lymphatic filariasis filarial nematodes nematodes Brugia malayi Wolbachia Aedes aegypti Microbiology QR1-502 Matthew Chung Laura E. Teigen Silvia Libro Robin E. Bromley Dustin Olley Nikhil Kumar Lisa Sadzewicz Luke J. Tallon Anup Mahurkar Jeremy M. Foster Michelle L. Michalski Julie C. Dunning Hotopp Drug Repurposing of Bromodomain Inhibitors as Potential Novel Therapeutic Leads for Lymphatic Filariasis Guided by Multispecies Transcriptomics
description	ABSTRACT To better understand the transcriptomic interplay of organisms associated with lymphatic filariasis, we conducted multispecies transcriptome sequencing (RNA-Seq) on the filarial nematode Brugia malayi, its Wolbachia endosymbiont wBm, and its laboratory vector Aedes aegypti across the entire B. malayi life cycle. In wBm, transcription of the noncoding 6S RNA suggests that it may be a regulator of bacterial cell growth, as its transcript levels correlate with bacterial replication rates. For A. aegypti, the transcriptional response reflects the stress that B. malayi infection exerts on the mosquito with indicators of increased energy demand. In B. malayi, expression modules associated with adult female samples consistently contained an overrepresentation of genes involved in chromatin remodeling, such as the bromodomain-containing proteins. All bromodomain-containing proteins encoded by B. malayi were observed to be upregulated in the adult female, embryo, and microfilaria life stages, including 2 members of the bromodomain and extraterminal (BET) protein family. The BET inhibitor JQ1(+), originally developed as a cancer therapeutic, caused lethality of adult worms in vitro, suggesting that it may be a potential therapeutic that can be repurposed for treating lymphatic filariasis. IMPORTANCE The current treatment regimen for lymphatic filariasis is mostly microfilaricidal. In an effort to identify new drug candidates for lymphatic filariasis, we conducted a three-way transcriptomics/systems biology study of one of the causative agents of lymphatic filariasis, Brugia malayi, its Wolbachia endosymbiont wBm, and its vector host Aedes aegypti at 16 distinct B. malayi life stages. B. malayi upregulates the expression of bromodomain-containing proteins in the adult female, embryo, and microfilaria stages. In vitro, we find that the existing cancer therapeutic JQ1(+), which is a bromodomain and extraterminal protein inhibitor, has adulticidal activity in B. malayi.
format	article
author	Matthew Chung Laura E. Teigen Silvia Libro Robin E. Bromley Dustin Olley Nikhil Kumar Lisa Sadzewicz Luke J. Tallon Anup Mahurkar Jeremy M. Foster Michelle L. Michalski Julie C. Dunning Hotopp
author_facet	Matthew Chung Laura E. Teigen Silvia Libro Robin E. Bromley Dustin Olley Nikhil Kumar Lisa Sadzewicz Luke J. Tallon Anup Mahurkar Jeremy M. Foster Michelle L. Michalski Julie C. Dunning Hotopp
author_sort	Matthew Chung
title	Drug Repurposing of Bromodomain Inhibitors as Potential Novel Therapeutic Leads for Lymphatic Filariasis Guided by Multispecies Transcriptomics
title_short	Drug Repurposing of Bromodomain Inhibitors as Potential Novel Therapeutic Leads for Lymphatic Filariasis Guided by Multispecies Transcriptomics
title_full	Drug Repurposing of Bromodomain Inhibitors as Potential Novel Therapeutic Leads for Lymphatic Filariasis Guided by Multispecies Transcriptomics
title_fullStr	Drug Repurposing of Bromodomain Inhibitors as Potential Novel Therapeutic Leads for Lymphatic Filariasis Guided by Multispecies Transcriptomics
title_full_unstemmed	Drug Repurposing of Bromodomain Inhibitors as Potential Novel Therapeutic Leads for Lymphatic Filariasis Guided by Multispecies Transcriptomics
title_sort	drug repurposing of bromodomain inhibitors as potential novel therapeutic leads for lymphatic filariasis guided by multispecies transcriptomics
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/1e447a65c7f547f7b29505baa9201b24
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Drug Repurposing of Bromodomain Inhibitors as Potential Novel Therapeutic Leads for Lymphatic Filariasis Guided by Multispecies Transcriptomics

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