Drug repurposing of bromodomain inhibitors as potential novel therapeutic leads for lymphatic filariasis guided by multi-species transcriptomics
Ontology highlight
ABSTRACT:
ORGANISM(S): Aedes aegypti Brugia malayi Wolbachia endosymbiont of Brugia malayi
PROVIDER: GSE139965 | GEO | 2019/11/20
REPOSITORIES: GEO
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Project description:Doxycycline treatment affects gene expression in Wolbachia and Brugia malayi adult female worms in vivo Two biological replicates of female RNA used for hybridization, in duplicate, to examine the gene expression changes in Wolbachia and Brugia
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Project description:The filarial nematodes Brugia malayi, Wuchereria bancrofti and Onchocerca volvulus cause elephantiasis, dermatitis and blindness, resulting in severe morbidity in developing countries. 1.3 billion people are at risk of infection. Targeting the essential Wolbachia endobacteria of filarial nematodes with doxycycline has proven to be an effective therapy, resulting in a block in embryogenesis and worm development, and macrofilaricidal effects. However, doxycycline is contraindicated for a large portion of the at-risk population. To identify new targets for anti-wolbachial therapy, understanding the molecular basis of the Wolbachia-filaria symbiosis is required. We performed cross-species hybridization by using the Brugia malayi microarray to identify differentially expressed genes in the rodent filaria Litomosoides sigmodontis after depletion of Wolbachia which therefore might have a role in symbiosis.
2010-04-07 | GSE20976 | GEO
Project description:Parasite biology, by its very nature, cannot be understood without integrating it with that of the host, nor can the host response be adequately explained without considering the activity of the parasite. However, due to experimental limitations, molecular studies of parasite-host systems have been predominantly one-sided investigations focusing on either of the partners. Here we conduct a joint dual RNA-seq time course analysis of filarial parasite and host mosquito to better understand the parasite processes underlying development in, and interaction with, the host tissue from the establishment of infection to the emergence of infective-stage larva. Using the Brugia malayi-Aedes aegypti system, we report the parasite gene transcription dynamics, which exhibit a highly ordered developmental program consisting of a series of cyclical and state-transitioning temporal patterns. And, we contextualize these parasite data in relation to the concurrent dynamics of the host transcriptome. Comparative analyses using uninfected tissues and different host strains reveal the influence of parasite development on the host gene transcription as well as the influence of host environment on the parasite gene transcription. Furthermore, we critically evaluate the life-cycle transcriptome of B. malayi by comparing developmental stages in the mosquito relative to those in the mammalian host, providing insight into gene expression changes underpinning the mosquito-borne parasitic lifestyle of this heteroxenous parasite. Time-course mRNA profiles of filarial parasite Brugia malayi and host mosqutio Aedes aegypti were generated by deep sequencing using Illumina GAIIx.
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Project description:Wolbachia endosymbiont of Brugia malayi strain:wBm Raw sequence reads
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Project description:Wolbachia pipientis is an intracellular symbiotic bacterium found in insects and arthropods. Wolbachia can decrease the vectorial capacity for various pathogens, such as the dengue virus, in Aedes aegypti. The purpose of this study was to determine the effect of Wolbachia (wMel strain) on the vectorial capacity of Ae. aegypti for Dirofilaria immitis. We analyzed gene expression patterns by RNA-seq in addition to the D. immitis infection phenotype in Ae. aegypti infected with and without wMel. Four Ae. aegypti strains, MGYP2.tet, MGYP2, Liverpol (LVP)-Obihiro (OB), and LVP-OB-wMel (OB-wMel) were analyzed for transcriptome comparison in Malpighian tubule at 2 days post infection. The correlation between Wolbachia infection, D. immitis infection phenotype and immune-related genes expression in Ae. aegypti was investigated.
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Project description:The filarial nematodes Brugia malayi, Wuchereria bancrofti and Onchocerca volvulus cause elephantiasis, dermatitis and blindness, resulting in severe morbidity in developing countries. 1.3 billion people are at risk of infection. Targeting the essential Wolbachia endobacteria of filarial nematodes with doxycycline has proven to be an effective therapy, resulting in a block in embryogenesis and worm development, and macrofilaricidal effects. However, doxycycline is contraindicated for a large portion of the at-risk population. To identify new targets for anti-wolbachial therapy, understanding the molecular basis of the Wolbachia-filaria symbiosis is required. We performed cross-species hybridization by using the Brugia malayi microarray to identify differentially expressed genes in the rodent filaria Litomosoides sigmodontis after depletion of Wolbachia which therefore might have a role in symbiosis. Female adult Litomosoides sigmodontis from patent infections were treated with tetracycline to deplete endosymbiotic Wolbachia bacteria. RNA from tetracycline-treated Litomosoides sigmodontis was compared to untreated age-matched control worms. This experiment was performed for three different timepoints: day 6, 15 and 36 of tetracycline treatment. One biological replicate was performed each with two technical replicates (dye-flip replicates).
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Project description:Wolbachia is a vertically transmitted intracellular bacteria that infect most than 60% of insect species. The strains wMelPop and wMel were introduced in the dengue virus vector Aedes aegypti, naturally not infected by Wolbachia. Recently, it was shown that those two strains inhibit dengue virus replication into their new host, A. aegypti (Moreira et al. 2009 and Walker et al. in preparation). The aim of this project is to look at the transcriptional response of Aedes aegypti to infection with wMel and wMelPop and try to find some genes or pathway potentially involved in the viral interference.Four laboratory lines of A. aegypti were used throughout this study. The PGYP1 and Mel2 lines were generated by transinfection with wMelPop and wMel strains respectively. PGYP1.tet and Mel2tet lines were treated with the antibiotic tetracycline and cured from Wolbachia infection (McMeniman et al., 2009 and Walker et al in preparation). The Mosquitoes were reared under standard laboratory conditions (26 ± 2 °C, 12:12 light/dark cycle, 75% relative humidity). Mosquito larvae were fed 0.1mg/larvae of TetraMin Tropical Tablets once a day. Adults were transferred to cages (measuring 30 x 30 x 30 cm) at emergence at 400 individuals per cage. Adults were supplied with a basic diet of 10% sucrose solution (Turley et al., 2009).
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Project description:Lymphatic filarial nematodes maintain a mutualistic association with the intracellular bacterium Wolbachia. Wolbachia populations expand following infection of the mammalian host, to support larval growth and development. Utilizing transcriptomic data from Brugia malayi over the first two weeks post-infection, we present an analysis of the biochemical pathways that are involved in Wolbachia population growth and regulation in support of larval development. In Wolbachia, we observe coordinated regulation of carbon metabolism with an alternating pattern of glycolysis and TCA cycle pathways reminiscent of the ‘Warburg effect’. Wolbachia's purine, pyrimidine and haem biosynthesis and Type IV secretion pathways are also upregulated and correlate with the upregulation of the nematode’s DNA replication pathway. In the nematode we observe up-regulation of the autophagy pathway, a key regulator of Wolbachia populations. These findings support a key role for nucleotide and haem provisioning from Wolbachia in support of the larval growth and development of its nematode host.
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