Albendazole reduces endoplasmic reticulum stress induced byEchinococcus multilocularisin mice
Authors: Weingartner Michael , Jebbawi Fadi , Wang Junhua , Stücheli Simon , Gottstein Bruno , Beldi Guido , Lundström-Stadelmann Britta , Odermatt Alex 
Published: February 2021

Background

Echinococcus multiloculariscauses alveolar echinococcosis (AE), a rising zoonotic disease in the northern hemisphere. Treatment of this fatal disease is limited to chemotherapy using benzimidazoles and surgical intervention, with relatively frequent disease recurrence in cases without radical surgery. Elucidating the molecular mechanisms underlyingE. multilocularisinfections and host-parasite interactions aids developing novel therapeutic options. This study explored an involvement of unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) duringE. multilocularisinfection in mice.

Methods

E. multilocularis-and mock-infected C57BL/6 mice were subdivided six weeks after infection into vehicle and albendazole (ABZ) treated groups. Eight weeks later, liver tissue was collected to examine mRNA, microRNA (miR) and protein expression of UPR- and ERS-related genes.

Results

E. multilocularisinfection upregulated UPR- and ERS-related proteins, including ATF6, CHOP, GRP78, ERP72, H6PD and calreticulin, whilst PERK and its target eIF2α were not affected, and IRE1α and ATF4 were downregulated. ABZ treatment inE. multilocularisinfected mice reversed the increased ATF6 and calreticulin protein expression, tended to reverse increased CHOP, GRP78, ERP72 and H6PD expression, and decreased ATF4 and IRE1α expression to levels seen in mock-infected mice. The expression of miR-146a-5p (downregulated by IRE1α) and miR-1839-5p (exhibiting a unique target site in the IRE1α 3’UTR) were significantly increased inE. multilocularisinfected mice, an effect reversed by ABZ treatment. Other miRs analyzed were not altered inE. multilocularisinfected mice.

Conclusions and Significance

AE causes UPR activation and ERS in mice. TheE. multilocularis-induced ERS was ameliorated by ABZ treatment, indicating its effectiveness to inhibit parasite proliferation and downregulate its activity status. ABZ itself did not affect UPR in control mice. Identified miR-146a-5p and miR-1839-5p might represent biomarkers ofE. multilocularisinfection. Modulation of UPR and ERS, in addition to ABZ administration, could be exploited to treatE. multilocularisinfection.

Author summary

Alveolar echinococcosis is a zoonotic disease caused by the fox tapewormEchinococcus multilocularis. Treatment of this fatal disease is limited to surgical intervention, preferably radical curative surgery if possible, and the use of parasitostatic benzimidazoles. It is not yet fully understood how the parasite can remain in the host’s tissue for prolonged periods, complicating the development of therapeutic applications. This work investigated an involvement of the unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) duringE. multilocularisinfection and upon treatment with albendazole (ABZ) in mice. The results revealed increased expression levels of the ERS sensor ATF6 and of downstream target genes in liver tissue ofE. multilocularis-compared to mock-infected mice. Additionally, H6PD, generating NADPH within the endoplasmic reticulum, and the lectin-chaperone calreticulin were increased inE. multilocularisinfected liver tissue while the expression of the ERS associated genes ATF4 and IRE1α were decreased. The miR-1839-5p and miR-146-p, linked to IRE1α, were elevated uponE. multilocularisinfection, offering potential as novel biomarkers of alveolar echinococcosis. The observed gene expression changes were at least partially reversed by ABZ treatment. Whether modulation of UPR and ERS targets can improve the therapy of alveolar echinococcosis remains to be investigated.