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

• Main Authors: 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
• Format: Article
• Language: English
• Published: American Society for Microbiology 2019-12-01
• Series: mSystems
• Subjects: lymphatic filariasis; filarial nematodes; nematodes; brugia malayi; wolbachia; aedes aegypti; mosquito; transcriptomics; rna-seq; multispecies rna-seq; bromodomain; bromodomain inhibitor; 6s rna; brugia; drug repurposing; neglected tropical disease; symbiosis
• Online Access: https://doi.org/10.1128/mSystems.00596-19

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.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.