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

• Published in: mSystems Vol. 4; no. 6
• Main Authors: Chung, Matthew, Teigen, Laura E, Libro, Silvia, Bromley, Robin E, Olley, Dustin, Kumar, Nikhil, Sadzewicz, Lisa, Tallon, Luke J, Mahurkar, Anup, Foster, Jeremy M, Michalski, Michelle L, Dunning Hotopp, Julie C
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 03.12.2019
• Subjects: Adults; Aedes aegypti; Animal behavior; Brugia malayi; Chromatin remodeling; Drug development; Embryos; filarial nematodes; Filariasis; Gene expression; Host-Microbe Biology; Kinases; Laboratories; Lethality; Life cycles; lymphatic filariasis; Lymphedema; Males; Mosquitoes; Nematodes; Proteins; Research Article; Ribonucleic acid; RNA; Thorax; Transcription; Transcriptomics; Tropical diseases; Wolbachia; 6S RNA; Brugia; bromodomain inhibitor; nematodes; mosquito; filarial nematodes; lymphatic filariasis; bromodomain; drug repurposing; multispecies RNA-Seq; Brugia malayi; RNA-Seq; Wolbachia; symbiosis; transcriptomics; Aedes aegypti; neglected tropical disease
• ISSN: 2379-5077; 2379-5077
• DOI: 10.1128/mSystems.00596-19

To better understand the transcriptomic interplay of organisms associated with lymphatic filariasis, we conducted multispecies transcriptome sequencing (RNA-Seq) on the filarial nematode , its endosymbiont Bm, and its laboratory vector across the entire life cycle. In Bm, 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 , the transcriptional response reflects the stress that infection exerts on the mosquito with indicators of increased energy demand. In , 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 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 , suggesting that it may be a potential therapeutic that can be repurposed for treating lymphatic filariasis. 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, , its endosymbiont Bm, and its vector host at 16 distinct life stages. upregulates the expression of bromodomain-containing proteins in the adult female, embryo, and microfilaria stages. , we find that the existing cancer therapeutic JQ1(+), which is a bromodomain and extraterminal protein inhibitor, has adulticidal activity in .