The parasitic nematodes Onchocerca volvulus and Brugia malayi are responsible for devastating human filarial infections in the developing world such as river blindness and lymphatic filariasis. The awarding of the 2015 Nobel Prize in Physiology or Medicine to Campbell and Omura ?for their discoveries concerning a novel therapy against infections caused by roundworm parasites highlights the success of drugs such as Ivermectin for mass administration programs to control transmission of these parasites. However, current drugs only target the early larval stage (microfilaria) and have no effect on the adult worms, which can live 8-15 years. Consequently, drugs have to be administered for 30-40 years to eradicate the parasite from an infected population. The emergence of drug resistance has recently appeared as a real threat. Furthermore, in areas where O. volvulus is co-endemic with the agent responsible for loiasis (Loa loa), targeting the microfilaria can lead to serious adverse events. The ?Achilles heel? of these worms is their endosymbiotic bacteria? Wolbachia?which are sensitive to antibiotics and thus offer a more expedient approach to controlling filarial infections. Killing the bacteria impedes parasite development, fecundity, and ultimately, survival within the human host. But using antibiotics as a mass drug administration strategy is not yet feasible. To date little is known concerning the respective contributions of each symbiotic partner to parasite growth. Here we propose a detailed characterization of the metabolic co-dependencies between the worm and its endosymbiont, to reveal critical enzymes that can be exploited for therapeutic intervention. This project seeks to use the genome information available for B. malayi, O. volvulus and their respective Wolbachia (wOv and wBm) to map out metabolic enzymes within pathways critical for microfilaria and adult parasite survival. We will launch a systematic analysis of metabolite flux within these pathways, integrating functional genomic datasets that capture the expression of enzymes by both worm and endosymbiont at key life cycle stages.
Aim 1 will reconstruct combined filarial-Wolbachia metabolic pathways by integrating stage-specific RNAseq and metabolomics data to construct detailed mathematical models of parasite metabolism. We will then prioritize 5- 10 enzymes to validate model predictions in the most tractable model, B. malayi.
Aim 2 will test the essentiality of these enzymes and examine resultant phenotypes by using RNA mediated interference (RNAi) to validate their essential functions on worm growth and survival. In parallel, for those enzymes with known chemical inhibitors, we will monitor the ability of such compounds to also impact worm growth and survival. Beyond their potential as lead compounds, such inhibitors may serve as molecular tools to further dissect pathway function. Our ultimate goal is to deliver a number of new candidate drug targets that may be exploited through existing drug development pipelines and lead to new macrofilaricidal drugs that target adult worms and can be used for elimination of filariasis.
Onchocerca volvulus and Brugia malayi are parasitic worms that cause river blindness and elephantiasis respectively; despite their huge burden on global health, there are no viable vaccines and drug treatments are of limited efficacy. In this project we will construct sophisticated models of their metabolism to identify essential enzymes that may be targeted for therapeutic intervention. Experimental validation of key targets will result in novel candidates that will feed into global drug development platforms.
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