Impairing the maintenance of germinative cells in Echinococcus multilocularis by targeting Aurora kinase

Background The 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 findings In 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/Significance Our 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. Author summary Alveolar echinococcosis (AE), caused by infection with the metacestode larvae of the tapeworm E. multilocularis, is a lethal disease in humans. A population of adult stem cells, called germinative cells, drive the cancer-like growth of the parasite within their host and are considered responsible for disease recurrence after therapy termination. Nevertheless, benzimidazoles, the current drugs of choice against AE, show limited effects on killing these cells. Here, we describe EmAURKA and EmAURKB, two Aurora kinase members that play essential roles in regulating E. multilocularis germinative cell mitosis, as promising drug targets for eliminating the population of germinative cells. 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.