title: On the importance of targeting parasite stem cells in anti-echinococcosis drug development.
abstract: The life-threatening diseases alveolar and cystic echinococcoses are caused by larvae of the tapeworms Echinococcus multilocularis and E. granulosus, respectively. In both cases, intermediate hosts, such as humans, are infected by oral uptake of oncosphere larvae, followed by asexual multiplication and almost unrestricted growth of the metacestode within host organs. Besides surgery, echinococcosis treatment relies on benzimidazole-based chemotherapy, directed against parasite beta-tubulin. However, since beta-tubulins are highly similar between cestodes and humans, benzimidazoles can only be applied at parasitostatic doses and are associated with adverse side effects. Mostly aiming at identifying alternative drug targets, the nuclear genome sequences of E. multilocularis and E. granulosus have recently been characterized, revealing a large number of druggable targets that are expressed by the metacestode. Furthermore, recent cell biological investigations have demonstrated that E. multilocularis employs pluripotent stem cells, called germinative cells, which are the only parasite cells capable of proliferation and which give rise to all differentiated cells. Hence, the germinative cells are the crucial cell type mediating proliferation of E. multilocularis, and most likely also E. granulosus, within host organs and should also be responsible for parasite recurrence upon discontinuation of chemotherapy. Interestingly, recent investigations have also indicated that germinative cells might be less sensitive to chemotherapy because they express a beta-tubulin isoform with limited affinity to benzimidazoles. In this article, we briefly review the recent findings concerning Echinococcus genomics and stem cell research and propose that future research into anti-echinococcosis drugs should also focus on the parasite's stem cell population.
authors.affiliation: Institute of Hygiene and Microbiology, University of Würzburg, Würzburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Brehm
authors.affiliation: Institute of Hygiene and Microbiology, University of Würzburg, Würzburg, Germany - Sección Bioquímica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Uriel
authors.initials: U
authors.lastname: Koziol
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004443:Echinococcosis / Q000188:drug therapy* / Q000469:parasitology; D004446:Echinococcus / Q000166:cytology / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D048210:Echinococcus multilocularis / Q000166:cytology / Q000187:drug effects; D023281:Genomics; D015801:Helminth Proteins / Q000037:antagonists & inhibitors; D006918:Hydroxyurea / Q000494:pharmacology / Q000627:therapeutic use; D007814:Larva; D058990:Molecular Targeted Therapy; D010274:Parasitology / Q000379:methods; D039904:Pluripotent Stem Cells / Q000187:drug effects*; D011621:Pteridines / Q000494:pharmacology / Q000627:therapeutic use; D059467:Transcriptome; D014404:Tubulin / Q000187:drug effects
chemical_list: D000871:Anthelmintics; C518477:BI 2536; D001562:Benzimidazoles; D015801:Helminth Proteins; D011621:Pteridines; D014404:Tubulin; D006918:Hydroxyurea