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Background  Alveolar echinococcosis (AE) is a life-threatening disease caused by larvae of the fox-tapeworm  Echinococcus multilocularis . Crucial to AE pathology is continuous infiltrative growth of the parasite's metacestode stage, which is driven by a population of somatic stem cells, called germinative cells. Current anti-AE chemotherapy using benzimidazoles is ineffective in eliminating the germinative cell population, thus leading to remission of parasite growth upon therapy discontinuation.    Methodology/Principal findings  We herein describe the characterization of EmPlk1, encoded by the gene  emplk1 , which displays significant homologies to members of the Plk1 sub-family of Polo-like kinases that regulate mitosis in eukaryotic cells. We demonstrate germinative cell-specific expression of  emplk1  by RT-PCR, transcriptomics, and  in situ  hybridization. We also show that EmPlk1 can induce germinal vesicle breakdown when heterologously expressed in  Xenopus  oocytes, indicating that it is an active kinase. This activity was significantly suppressed in presence of BI 2536, a Plk1 inhibitor that has been tested in clinical trials against cancer. Addition of BI 2536 at concentrations as low as 20 nM significantly blocked the formation of metacestode vesicles from cultivated  Echinococcus  germinative cells. Furthermore, low concentrations of BI 2536 eliminated the germinative cell population from mature metacestode vesicles  in vitro , yielding parasite tissue that was no longer capable of proliferation.    Conclusions/Significance  We conclude that BI 2536 effectively inactivates  E. multilocularis  germinative cells in parasite larvae  in vitro  by direct inhibition of EmPlk1, thus inducing mitotic arrest and germinative cell killing. Since germinative cells are decisive for parasite proliferation and metastasis formation within the host, BI 2536 and related compounds are very promising compounds to complement benzimidazoles in AE chemotherapy.

Targeting Echinococcus multilocularis Stem Cells by Inhibition of the Polo-Like Kinase EmPlk1