Drug repurposing of bromodomain inhibitors as potential novel therapeutic leads for lymphatic filariasis guided by multispecies transcriptomics
Author
Chung, M.Bromley, R.E.
Olley, D.
Kumar, N.
Sadzewicz, L.
Tallon, L.J.
Mahurkar, A.
Dunning Hotopp, J.C.
Date
2019Journal
mSystemsPublisher
American Society for MicrobiologyType
Article
Metadata
Show full item recordAbstract
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. Copyright 2019 Chung et al.Sponsors
This project was funded by federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under grant number U19AI110820.Keyword
6S RNAAedes aegypti
Bromodomain
Bromodomain inhibitor
Brugia
Brugia malayi
Drug repurposing
Filarial nematodes
Lymphatic filariasis
Mosquito
Multispecies RNA-Seq
Neglected tropical disease
Nematodes
RNA-Seq
Symbiosis
Transcriptomics
Wolbachia
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https://www.scopus.com/inward/record.uri?eid=2-s2.0-85078405429&doi=10.1128%2fmSystems.00596-19&partnerID=40&md5=07c9b6a7c115d268e3e04f07bf4a867f; http://hdl.handle.net/10713/11670ae974a485f413a2113503eed53cd6c53
10.1128/mSystems.00596-19