Metformin promotes autophagy in Echinococcus granulosus larval stage

Abstract

Cystic echinococcosis is a neglected parasitic disease caused by the larval stage of Echinococcus granulosus for which an effective treatment is not yet available. Since autophagy constitutes a homeostatic mechanism during stress, either inhibition or activation of its activity might be detrimental for survival of the parasite. Amongst the critical molecules that regulate autophagy, TOR, AMPK and sirtuins are the best characterized ones. Previously, we have identified the autophagic machinery, the occurrence of TORC1-controlled events, and the correlation 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 to metformin (Met), a drug that indirectly activates Eg-AMPK and induces energy stress. In this work, we demonstrate that Met induces autophagy in the E. granulosus larval stage. Electron microscopy analysis revealed the presence of autophagic structures in Met-treated protoscoleces. In accordance with these findings, the autophagic marker Eg-Atg8 as well as the transcriptional expression of Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16 genes were significantly up-regulated in Met-treated parasites. The induction of the autophagic process was concomitant with Eg-foxO over-expression and its nuclear localization, which could be correlated with the transcriptional regulation of this pathway. On the other hand, the expression of Eg-AKT and Eg-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 anti-echinococcal effects of this drug. The understanding of the regulatory mechanisms of this pathway in E. granulosus represents a solid basis for choosing appropriate targets for new chemotherapeutic agents.

Endoplasmic Reticulum Stress, a Target for Drug Design and Drug Resistance in Parasitosis

“…Echinococcus granulosus is the causative cestode of hydatidosis or cystic echinococcosis (CE) and is a worldwide zoonotic infection that affects many organs in human and mammals ( Loos et al, 2018 ). Nicolao et al (2017) have identified the ortholog of IRE2, XBP1, and ATF6 in the genome of E. granulosus , but the ortholog of PERK/ATF4 was not found.…”

Synergism therapeutic and immunoregulatory effects of Albendazole + rAd-mIL-28B against Echinococcosis in experiment-infected mice with protoscoleces

“…The eggs of E. granulosus were ingested by the intermediate hosts (sheep and cattle), developing into a hydatid cyst, which containing protoscoleces (PSCs). The definitive hosts (such as dogs) got infected by swallowing the tainted tissue from intermediate host and PSCs can develop into adult tapeworms in small intestine, residing for a long time [ 2 ]. It reported that the echinococcal cysts can survive in human body for 20–25 years, even as long as 50 years [ 3 ], which caused the long-term damage and burden in patients.…”

“…CE also is one of the neglected parasitic diseases in the world, its effective treatment is not yet available [ 2 ]. Since the early 1970s, benzimidazoles have been shown to inhibit cysts growth and used to treat CE [ 5 ].…”

The excretory/secretory products of fifth-stage larval Angiostrongylus cantonensis induces autophagy via the Sonic hedgehog pathway in mouse brain astrocytes

“…In parasitic helminths, recent studies have revealed that the inhibition of autophagy or excess autophagy can induce cell apoptosis in Echinococcus granulosus. It can provide appropriate targets for new chemotherapeutic drugs for parasitic helminths [26].…”