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Omega-1 knockdown in Schistosoma mansoni eggs by lentivirus transduction reduces granuloma size in vivo.

ABSTRACT: Schistosomiasis, one of the most important neglected tropical diseases worldwide, is caused by flatworms (blood flukes or schistosomes) that live in the bloodstream of humans. The hepatointestinal form of this debilitating disease results from a chronic infection with Schistosoma mansoni or Schistosoma japonicum. No vaccine is available to prevent schistosomiasis, and treatment relies predominantly on the use of a single drug, praziquantel. In spite of considerable research effort over the years, very little is known about the complex in vivo events that lead to granuloma formation and other pathological changes during infection. Here we use, for the first time, a lentivirus-based transduction system to deliver microRNA-adapted short hairpin RNAs (shRNAmirs) into the parasite to silence and explore selected protein-encoding genes of S. mansoni implicated in the disease process. This gene-silencing system has potential to be used for functional genomic-phenomic studies of a range of socioeconomically important pathogens.

SUBMITTER: Hagen J

PROVIDER: S-EPMC4243216 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Omega-1 knockdown in Schistosoma mansoni eggs by lentivirus transduction reduces granuloma size in vivo.

Hagen Jana J Young Neil D ND Every Alison L AL Pagel Charles N CN Schnoeller Corinna C Scheerlinck Jean-Pierre Y JP Gasser Robin B RB Kalinna Bernd H BH

Nature communications 20141117

Schistosomiasis, one of the most important neglected tropical diseases worldwide, is caused by flatworms (blood flukes or schistosomes) that live in the bloodstream of humans. The hepatointestinal form of this debilitating disease results from a chronic infection with Schistosoma mansoni or Schistosoma japonicum. No vaccine is available to prevent schistosomiasis, and treatment relies predominantly on the use of a single drug, praziquantel. In spite of considerable research effort over the years ...[more]

PMID: 25400038

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Project description:Background & aimsSchistosomiasis is a parasitic infection which affects more than 200 million people globally. Schistosome eggs, but not the adult worms, are mainly responsible for schistosomiasis-specific morbidity in the liver. It is unclear if S. mansoni eggs consume host metabolites, and how this compromises the host parenchyma.MethodsMetabolic reprogramming was analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging, liquid chromatography with high-resolution mass spectrometry, metabolite quantification, confocal laser scanning microscopy, live cell imaging, quantitative real-time PCR, western blotting, assessment of DNA damage, and immunohistology in hamster models and functional experiments in human cell lines. Major results were validated in human biopsies.ResultsThe infection with S. mansoni provokes hepatic exhaustion of neutral lipids and glycogen. Furthermore, the distribution of distinct lipid species and the regulation of rate-limiting metabolic enzymes is disrupted in the liver of S. mansoni infected animals. Notably, eggs mobilize, incorporate, and store host lipids, while the associated metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes. Administration of reactive oxygen species scavengers ameliorates these deleterious effects.ConclusionsOur findings indicate that S. mansoni eggs completely reprogram lipid and carbohydrate metabolism via soluble factors, which results in oxidative stress-induced cell damage in the host parenchyma.Impact and implicationsThe authors demonstrate that soluble egg products of the parasite S. mansoni induce hepatocellular reprogramming, causing metabolic exhaustion and a strong redox imbalance. Notably, eggs mobilize, incorporate, and store host lipids, while the metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes, independent of the host's immune response. S. mansoni eggs take advantage of the host environment through metabolic reprogramming of hepatocytes and enterocytes. By inducing DNA damage, this neglected tropical disease might promote hepatocellular damage and thus influence international health efforts.

Project description:Protein variation in blood-dwelling schistosome worms generated by differential splicing of micro-exon gene transcripts. The infective schistosome cercaria develops from an undifferentiated germ ball within the daughter sporocyst in the molluscan host, during which considerable morphological development and synthesis of proteins essential for infection occurs. The free-living, non-feeding cercaria is notable for its swimming and host location behaviour. On contact with host skin it rapidly penetrates, replaces its tegument surface membranes, and begins body remodelling, before crossing the dermis to exit the skin via a blood vessel. Such a ‘violent’ transition from snail to fresh water to mammalian host should be accompanied by remarkable changes in the patterns of gene expression. All gene models from version E of the S. mansoni genome (www.GeneDB.org) were incorporated into a 350K feature Roche-NimbleGen, high-density oligonucleotide array. From a map-ordered list, every 13th 50mer was chosen as a probe. Double-stranded cDNA from three biological replicates each of germ balls, cercariae, and day 3 schistosomula was hybridised to the array without amplification. Statistical analysis was carried out using programmes from the Bioconductor suite (Gentleman et al. 2004 Genome Biol 5(10):R80). More than 1000 loci were shown to be differentially expressed in each of the comparisons between the three life cycle stages. Gene ontology (GO) analysis was then carried out to discover the categories enriched in each stage. In addition custom categories based on biological function (e.g. stress response) or parasite tissue (e.g. tegument) were analysed. Three biological replicates each of germ balls, cercariae, day 3 in vitro cultured schistosomula, and eggs were used. No technical replicates were included. This is the first genome-wide microarray platform for S. mansoni. It was used to investigate the gene expression patterns of the above lifecycle stages. The first three are the stages before, during and after penetration of mammalian host skin.

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Omega-1 knockdown in Schistosoma mansoni eggs by lentivirus transduction reduces granuloma size in vivo.

Publications

Omega-1 knockdown in Schistosoma mansoni eggs by lentivirus transduction reduces granuloma size in vivo.

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