Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

Abstract

The filarial nematode Brugia malayi represents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteria Wolbachia—present in many filariae—which is vital to the worm. Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but have only been applied to multicellular eukaryotic organisms more recently. Here, we present iDC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 102 reactions essential to the survival of B. malayi. We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.

MetaPro: A scalable and reproducible data processing and analysis pipeline for metatranscriptomic investigation of microbial communities

“…Since annotations based on simple similarity searches can yield false positive rates of up to 50% 53 , MetaPro relies on a robust approach that combines predictions from DETECT 36 , with those from PRIAM 54 that are also confirmed by sequence similarity searches against the Swiss-Prot database 55 . This approach has been shown to significantly outperform sequence similarity searches and has been effectively applied in a number of settings 56-61…”

Toward novel treatment against filariasis: Insight into genome-wide co-evolutionary analysis of filarial nematodes and Wolbachia

“…However, Wolbachia can affect lipid profiles in arthropod host and can modulate viral infection ( Caragata et al, 2013 ; Molloy et al, 2016 ). Nematode and bacteria are capable of glyoxylation shunting which shortcuts the TCA cycle and utilizes fatty acid as a source of acetyl-CoA for gluconeogenesis and energy metabolism ( International Helminth Genomes Consortium, 2019 ; Curran et al, 2020 ). Fatty acid would be required for growth and reproduction, and it is also an essential precursor for the production of steroid hormones including reproductive hormones.…”

Metabolic Modeling to Interrogate Microbial Disease: A Tale for Experimentalists

“…Metabolic modeling has also been used to find potential drug targets for parasites causing diseases in humans ( Curran et al, 2020 ). The parasitic worm Brugia malayi is one of the causes of lymphatic filariasis (also known as elephantiasis) and is transmitted through blood-sucking mosquitoes; infection with this parasite can result in the swelling of limbs via chronic leakage of lymph into tissues ( Chandy et al, 2011 ).…”

“…Recent studies have indicated that targeting Wolbachia , an endosymbiotic microorganism implicated in B. malayi fitness and its reproduction cycle, might represent an new therapeutic avenue ( Taylor et al, 2013 ). In an attempt to identify potential drugs aimed at Wolbachia that would result in its elimination of B. malayi , Curran and colleagues reconstructed a GEM of the worm and identified 102 essential metabolic reactions predicted to be essential for the survival of the worm ( Curran et al, 2020 ). By filtering out metabolic reactions for which no experimental expression data are available as well as the pathways with homology to human metabolic reactions, in silico modeling predicted that the enzymes 1-deoxy-D-xylulose 5-phosphate reductoisomerase, fructose biphosphatase and an adenylate kinase represent potential Wolbachia enzymes to be targeted.…”

“…By filtering out metabolic reactions for which no experimental expression data are available as well as the pathways with homology to human metabolic reactions, in silico modeling predicted that the enzymes 1-deoxy-D-xylulose 5-phosphate reductoisomerase, fructose biphosphatase and an adenylate kinase represent potential Wolbachia enzymes to be targeted. Interestingly, the drugs Fosmidomycin and tenofovir (both clinically approved) specifically target those enzymes and were experimentally confirmed to reduce the abundance of Wolbachia in B. malayi , negatively impacting the worm ( Curran et al, 2020 ).…”