Abstract
Worldwide, more than 1 billion people are affected by infestations with soil-transmitted helminths and also in veterinary medicine helminthiases are a severe threat to livestock due to emerging resistances against the common anthelmintics. Proanthocyanidins have been increasingly investigated for their anthelmintic properties, however, except for an interaction with certain proteins of the nematodes, not much is known about their mode of action. To investigate the anthelmintic activity on a molecular level, a transcriptome analysis was performed in Caenorhabditis elegans after treatment with purified and fully characterized oligomeric procyanidins (OPC). The OPCs had previously been obtained from a hydro-ethanolic (1:1) extract from the leaves of Combretum mucronatum, a plant which is traditionally used in West Africa for the treatment of helminthiasis, therefore, also the crude extract was included in the study. Significant changes in differential gene expression were observed mainly for proteins related to the intestine, many of which were located extracellularly or within cellular membranes. Among the up-regulated genes, several hitherto undescribed orthologues of structural proteins in humans were identified, but also genes that are potentially involved in the worms’ defense against tannins. For example, T22D1.2, an orthologue of human basic salivary proline-rich protein (PRB) 2, and numr-1 (nuclear localized metal responsive) were found to be strongly up-regulated. Down-regulated genes were mainly associated with lysosomal activity, glycoside hydrolysis or the worms’ innate immune response. No major differences were found between the groups treated with purified OPCs versus the crude extract. Investigations using GFP reporter gene constructs of T22D1.2 and numr-1 corroborated the intestine as the predominant site of the anthelmintic activity. The current findings support previous hypotheses of OPCs interacting with intestinal surface proteins and provide the first insights into the nematode’s response to OPCs on a molecular level as a base for the identification of future drug targets.
Highlights
Worldwide, more than 1.5 billion people are affected by infestations with intestinal nematodes [1,2] and in veterinary medicine, helminths pose a severe threat to livestock [3,4,5]
From the leaves of Combretum mucronatum, a herbal remedy which is widely used as anthelmintic remedy in West Africa [44], an extract was obtained which was strongly enriched with oligomeric procyanidins (OPC)
Procyanidins in C. elegans was obtained, which contained a mixture of oligomeric procyanidins, which recently have been characterized in detail [45]
Summary
More than 1.5 billion people are affected by infestations with intestinal nematodes [1,2] and in veterinary medicine, helminths pose a severe threat to livestock [3,4,5]. Condensed and hydrolysable tannins have been reported to cause a variety of detrimental effects in vitro on different nematode species at different life stages These include the inhibition of egg hatch, larval exsheathment, larval migration, feeding and larval development as well as lethal effects in adults (for review see [12,14,18]). Several microscopic investigations have indicated that in particular the nematode cuticle, the buccal cavity and the intestine provided potential binding sites for tannins [12,26,27,28,29,30,31,32,33,34] Flavonoids, another major subgroup of polyphenols, exert direct anthelmintic effects in some cases [35,36,37,38,39] and no effect in others [33], depending on the exact flavonoid structure and the test system used [40,41,42,43]. The current study aims at investigating the molecular effects of a polyphenol rich extract and isolated procyanidins from the leaves of Combretum mucronatum, a plant traditionally used in West Africa for the treatment of intestinal helminthiasis [44], by transcriptome analysis using the model nematode Caenorhabditis elegans
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