title: Herbimycin A suppresses mitotic activity and egg production of female Schistosoma mansoni.
abstract: The eggs of the endoparasite Schistosoma are the causative agent of schistosomiasis, an important disease of humans, which is endemic in (sub-) tropical regions. The absence of a vaccine with sufficient protective qualities and increasing resistance to approved and established drugs like praziquantel, justify the exploration of novel ways to fight schistosomes. Our strategy is based on interference with the sexual maturation of the female. Prerequisites for gonad development in adult females are a continuous pairing contact with the male and significantly increased mitotic activity. In this study we show that the male governs sexual maturation of the female, as the separation of couples causes a clear reduction of female mitotic activity and, consequently, egg production. We demonstrate that treatment of schistosomes with Herbimycin A, an inhibitor of protein tyrosine kinases (PTKs), mimics the separation of couples as the drug blocks mitotic activity and egg production of paired females. However, the synthesis of the eggshell precursor protein p14 is elevated. Furthermore, we show for the first time in invertebrates that Herbimycin A decreases tyrosine phosphorylation and PTK stability in schistosomes. Summarised, our data provide evidence that PTKs have key functions in regulating gonad development, eggshell gene expression and, consequently, egg production. Therefore, we suggest envisaging schistosome PTKs as novel targets for strategies to combat schistosomiasis.
authors.affiliation: Institut für Genetik, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Knobloch
authors.forename: Werner
authors.initials: W
authors.lastname: Kunz
authors.forename: Christoph G
authors.initials: CG
authors.lastname: Grevelding
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D018509:DNA, Helminth / Q000096:biosynthesis; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004527:Egg Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D015801:Helminth Proteins / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008297:Male; D008938:Mitosis / Q000187:drug effects*; D010270:Parasite Egg Count; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017828:Rifabutin / Q000031:analogs & derivatives; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000502:physiology; D012997:Solvents / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D018509:DNA, Helminth; D004527:Egg Proteins; D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D047029:Lactams, Macrocyclic; D011498:Protein Precursors; D012997:Solvents; C015753:chorion proteins; D017828:Rifabutin; D014443:Tyrosine; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D004121:Dimethyl Sulfoxide