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

Autor: Weingartner, Michael, St��cheli, Simon, Jebbawi, Fadi, Gottstein, Bruno, Beldi, Guido, Lundstr��m-Stadelmann, Britta, Wang, Junhua, Odermatt, Alex
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Physiology
RC955-962
Protein Expression
Cancer Treatment
Endoplasmic Reticulum
Mice
Medical Conditions
Arctic medicine. Tropical medicine
Immune Physiology
Medicine and Health Sciences
610 Medicine & health
Immune Response
Innate Immune System
Secretory Pathway
630 Agriculture
Animal Models
Endoplasmic Reticulum Stress
Experimental Organism Systems
Oncology
Cell Processes
Helminth Infections
590 Animals (Zoology)
Cytokines
Public aspects of medicine
RA1-1270
Cellular Structures and Organelles
Research Article
Neglected Tropical Diseases
Echinococcosis
Hepatic
Immunology
Mouse Models
Cytokine Therapy
Research and Analysis Methods
Albendazole
Model Organisms
Signs and Symptoms
Echinococcosis
Parasitic Diseases
Gene Expression and Vector Techniques
Animals
Molecular Biology Techniques
Molecular Biology
Inflammation
Molecular Biology Assays and Analysis Techniques
Biology and Life Sciences
Anticestodal Agents
Cell Biology
500 Science
Molecular Development
Tropical Diseases
Mice
Inbred C57BL
Immune System
Chronic Disease
Animal Studies
570 Life sciences
biology
Echinococcus multilocularis
Clinical Medicine
Developmental Biology
Zdroj: PLoS Neglected Tropical Diseases
PLoS Neglected Tropical Diseases, Vol 16, Iss 1, p e0009192 (2022)
Weingartner, Michael; Stücheli, Simon; Jebbawi, Fadi; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Wang, Junhua; Odermatt, Alex (2022). Albendazole reduces hepatic inflammation and endoplasmic reticulum-stress in a mouse model of chronic Echinococcus multilocularis infection. PLoS neglected tropical diseases, 16(1), e0009192. Public Library of Science 10.1371/journal.pntd.0009192
ISSN: 1935-2735
1935-2727
DOI: 10.1371/journal.pntd.0009192
Popis: Background Echinococcus 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. Methods E. multilocularis- and mock-infected C57BL/6 mice were subdivided into vehicle, albendazole (ABZ) and anti-programmed death ligand 1 (αPD-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. Results E. 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 eIF2α were not affected, and IRE1α 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)-1β, IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in the liver of infected mice. Similar to ABZ, αPD-L1 immune-treatment tended to reverse the increased CHOP and decreased ATF4 and IRE1α expression levels. Conclusions and significance AE caused chronic inflammation, UPR activation and ERS in mice. The E. multilocularis-induced inflammation and consecutive ERS was ameliorated by ABZ and αPD-L1 treatment, indicating their effectiveness to inhibit parasite proliferation and downregulate its activity status. Neither ABZ nor αPD-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 summary Alveolar 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 (αPD-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 IRE1α 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-1β, IL-6, TNF-α and IFN-γ. PD-L1 blockade reversed the AE-induced changes of UPR and ERS associated proteins CHOP, ATF4 and IRE1α. 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.
Databáze: OpenAIRE
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