CONICET | Buscador de Institutos y Recursos Humanos

Cystic echinococcosis is a neglected parasitic disease caused by the larval stage ofEchinococcus granulosus for which an effective treatment is not yet available. Since autophagyconstitutes a homeostatic mechanism during stress, either inhibition or activation of its activitymight be detrimental for survival of the parasite. Amongst the critical molecules that regulateautophagy, TOR, AMPK and sirtuins are the best characterized ones. Previously, we haveidentified the autophagic machinery, the occurrence of TORC1-controlled events, and theACCEPTED MANUSCRIPT3correlation between autophagy and the activation of the unfolded protein response in E.granulosus larval stage. In addition, we have demonstrated that the parasite is susceptible tometformin (Met), a drug that indirectly activates Eg-AMPK and induces energy stress. In thiswork, we demonstrate that Met induces autophagy in the E. granulosus larval stage. Electronmicroscopy analysis revealed the presence of autophagic structures in Met-treatedprotoscoleces. In accordance with these findings, the autophagic marker Eg-Atg8 as well as thetranscriptional expression of Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16 genes were significantlyup-regulated in Met-treated parasites. The induction of the autophagic process was concomitantwith Eg-foxO over-expression and its nuclear localization, which could be correlated with thetranscriptional regulation of this pathway. On the other hand, the expression of Eg-AKT andEg-Sirts suggests a possible participation of these conserved proteins in the regulation of Eg-FoxO. Therefore, through pharmacological activation of the AMPK-FoxO signaling pathway,Met could play a role in the death of the parasite contributing to the demonstrated antiechinococcaleffects of this drug. The understanding of the regulatory mechanisms of thispathway in E. granulosus represents a solid basis for choosing appropriate targets for newchemotherapeutic agents.

enviar mensaje