Albendazole reduces hepatic inflammation and endoplasmic reticulum-stress in a mouse model of chronic Echinococcus multilocularis infection

BackgroundEchinococcus multilocularis causes 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 frequent disease recurrence in cases without radical surgery. Elucidating the molecular mechanisms underlying E. multilocularis infections and host-parasite interactions ultimately aids developing novel therapeutic options. This study explored an involvement of unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) during E. multilocularis infection in mice. MethodsE. multilocularis- and mock-infected C57BL/6 mice were subdivided into vehicle, albendazole (ABZ) and anti-programmed death ligand 1 (alpha PD-L1) treated groups. To mimic a chronic infection, treatments of mice started six weeks post i.p. infection and continued for another eight weeks. Liver tissue was then collected to examine inflammatory cytokines and the expression of UPR- and ERS-related genes. ResultsE. multilocularis infection led to an upregulation of UPR- and ERS-related proteins in the liver, including ATF6, CHOP, GRP78, ERp72, H6PD and calreticulin, whilst PERK and its target eIF2 alpha were not affected, and IRE1 alpha and ATF4 were downregulated. ABZ treatment in E. multilocularis infected mice reversed, or at least tended to reverse, these protein expression changes to levels seen in mock-infected mice. Furthermore, ABZ treatment reversed the elevated levels of interleukin (IL)-1 beta, IL-6, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in the liver of infected mice. Similar to ABZ, alpha PD-L1 immune-treatment tended to reverse the increased CHOP and decreased ATF4 and IRE1 alpha expression levels. Conclusions and significanceAE caused chronic inflammation, UPR activation and ERS in mice. The E. multilocularis-induced inflammation and consecutive ERS was ameliorated by ABZ and alpha PD-L1 treatment, indicating their effectiveness to inhibit parasite proliferation and downregulate its activity status. Neither ABZ nor alpha PD-L1 themselves affected UPR in control mice. Further research is needed to elucidate the link between inflammation, UPR and ERS, and if these pathways offer potential for improved therapies of patients with AE. Author summaryAlveolar echinococcosis (AE) is a zoonotic disease, characterized by chronic progressive hepatic damage caused by the continuous tumor-like proliferation of the larval stage (metacestode) of the fox tapeworm Echinococcus 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) during E. multilocularis infection and upon treatment with either albendazole (ABZ) or anti-programmed death ligand-1 (alpha PD-L1) in mice. The results revealed increased expression levels of the ERS sensor ATF6 and of downstream target genes in liver tissue of E. multilocularis- compared to mock-infected mice. Additionally, hexose-6-phosphate dehydrogenase (H6PD), generating NADPH within the endoplasmic reticulum, and the lectin-chaperone calreticulin were increased in E. multilocularis infected liver tissue while the expression of the ERS associated genes ATF4 and IRE1 alpha were decreased. The observed gene expression changes were at least partially reversed by ABZ treatment, which also reduced the AE-induced increase of the inflammatory cytokines IL-1 beta, IL-6, TNF-alpha and IFN-gamma. PD-L1 blockade reversed the AE-induced changes of UPR and ERS associated proteins CHOP, ATF4 and IRE1 alpha. Further investigation is needed to elucidate the link between inflammation and ERS in human patients with AE and whether modulation of these pathways may lead to improved therapy.

Automated summary

Infection with Echinococcus multilocularis induces UPR and ERS in mice, which can be ameliorated by treatment with albendazole or alpha PD-L1. These treatments reverse the changes in protein expression levels and inflammatory cytokines induced by the infection, offering potential for improved therapies for patients with AE.