Abstract
BackgroundThe tumor-like growth of the metacestode larvae of the tapeworm E. multilocularis causes human alveolar echinococcosis, a severe disease mainly affecting the liver. The germinative cells, a population of adult stem cells, are crucial for the larval growth and development of the parasite within the hosts. Maintenance of the germinative cell pools relies on their abilities of extensive proliferation and self-renewal, which requires accurate control of the cell division cycle. Targeting regulators of the cell division progression may impair germinative cell populations, leading to impeded parasite growth.Methodology/Principal findingsIn this study, we describe the characterization of EmAURKA and EmAURKB, which display significant similarity to the members of Aurora kinases that are essential mitotic kinases and play key roles in cell division. Our data suggest that EmAURKA and EmAURKB are actively expressed in the germinative cells of E. multilocularis. Treatment with low concentrations of MLN8237, a dual inhibitor of Aurora A and B, resulted in chromosomal defects in the germinative cells during mitosis, while higher concentrations of MLN8237 caused a failure in cytokinesis of the germinative cells, leading to multinucleated cells. Inhibition of the activities of Aurora kinases eventually resulted in depletion of the germinative cell populations in E. multilocularis, which in turn caused larval growth inhibition of the parasite.Conclusions/SignificanceOur data demonstrate the vital roles of Aurora kinases in the regulation of mitotic progression and maintenance of the germinative cells in E. multilocularis, and suggest Aurora kinases as promising druggable targets for the development of novel chemotherapeutics against human alveolar echinococcosis.
Highlights
Alveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is considered as the most lethal helminthiasis
We show that targeting E. multilocularis Aurora kinases by small molecular inhibitor MLN8237 causes severe mitotic defects and eventually impairs the viability of germinative cells, leading to larval growth inhibition of the parasite in vitro
Our study suggests that targeting mitosis by MLN8237 or related compounds offers possibilities for germinative cell killing and we hope this will help in exploring novel therapeutic strategies against the disease
Summary
Alveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is considered as the most lethal helminthiasis. Humans become infected by accidentally ingesting infectious eggs, which contain oncospheres and develop into cyst-like metacestode vesicles mainly in the liver. The protoscoleces are generated in the metacestode vesicles through asexual multiplication, and either mature into adult tapeworms if ingested by the definitive host (canids) or develop into metacestode vesicles when distributed in the intermediate host [1]. The ideal option for human AE treatment to date is surgery, which is always accompanied by chemotherapy. In cases where surgery is not possible, chemotherapy remains the only option [2]. Current anti-AE chemotherapy mainly relies on the benzimidazole carbamate derivatives albendazole and mebendazole. These drugs are only parasitostatic rather than parasiticidal, and the treatment usually needs years or even the life-long uptake of drugs. Novel chemotherapeutic options against AE have to be pursued [3,4]
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