Dataset Information

Albendazole increases the inflammatory response and the amount of Em2-positive small particles of Echinococcus multilocularis (spems) in human hepatic alveolar echinococcosis lesions.

ABSTRACT:

Background

Alveolar echinococcosis (AE) is caused by the metacestode stage of Echinococcus multilocularis. The inflammatory response to this infection is influenced by the interaction of the parasite with the host. We aimed to analyze human liver lesions infected with Echinococcus multilocularis and the changes of the cellular infiltrates during albendazole (ABZ) treatment.

Methodology/principal findings

We analyzed liver tissue samples from 8 untreated patients, 5 patients treated with two daily doses of 400 mg ABZ for up to two months and 7 patients treated for more than two months with the same ABZ therapy. A broad panel of monoclonal antibodies was used to characterize the lesion by immunohistochemistry. A change in the cellular infiltrate was observed between the different chemotherapy times. During the initial phases of treatment an increase in CD15+ granulocytes and CD68+ histocytes as well as in small particles of Echinococcus multilocularis (spems) was observed in the tissue surrounding the metacestode. Furthermore, we observed an increase in CD4+ T cells, CD20+ B cells and CD38+ plasma cells during a longer duration of treatment.

Conclusions/significance

ABZ treatment of AE leads to morphological changes characterized by an initial, predominantly acute, inflammatory response which is gradually replaced by a response of the adaptive immune system.

SUBMITTER: Ricken FJ

PROVIDER: S-EPMC5462468 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Albendazole increases the inflammatory response and the amount of Em2-positive small particles of Echinococcus multilocularis (spems) in human hepatic alveolar echinococcosis lesions.

Ricken Franz J FJ Nell Juliane J Grüner Beate B Schmidberger Julian J Kaltenbach Tanja T Kratzer Wolfgang W Hillenbrand Andreas A Henne-Bruns Doris D Deplazes Peter P Moller Peter P Kern Peter P Barth Thomas F E TFE

PLoS neglected tropical diseases 20170525 5

<h4>Background</h4>Alveolar echinococcosis (AE) is caused by the metacestode stage of Echinococcus multilocularis. The inflammatory response to this infection is influenced by the interaction of the parasite with the host. We aimed to analyze human liver lesions infected with Echinococcus multilocularis and the changes of the cellular infiltrates during albendazole (ABZ) treatment.<h4>Methodology/principal findings</h4>We analyzed liver tissue samples from 8 untreated patients, 5 patients treate ...[more]

PMID: 28542546

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Project description:BackgroundAlveolar (AE) and cystic echinococcosis (CE) in humans are caused by the metacestode of the tapeworms Echinococcus multilocularis and Echinococcus granulosus sensu lato (s.l.). Immunohistochemistry with the monoclonal antibodies (mAb) Em2G11, specific for AE, and the mAb EmG3, specific for AE and CE, is an important pillar of the histological diagnosis of these two infections. Our aim was to further evaluate mAb EmG3 in a diagnostic setting and to analyze in detail the localization, distribution, and impact of small particles of Echinococcus multilocularis (spems) and small particles of Echinococcus granulosus s.l. (spegs) on lymph nodes.Methodology/principal findingsWe evaluated the mAb EmG3 in a cohort of formalin-fixed, paraffin embedded (FFPE) specimens of AE (n = 360) and CE (n = 178). These samples originated from 156 AE-patients and 77 CE-patients. mAb EmG3 showed a specific staining of the metacestode stadium of E. multilocularis and E. granulosus s.l. and had a higher sensitivity for spems than mAb Em2G11. Furthermore, we detected spegs in the surrounding host tissue and in almost all tested lymph nodes (39/41) of infected patients. 38/47 lymph nodes of AE showed a positive reaction for spems with mAb EmG3, whereas 29/47 tested positive when stained with mAb Em2G11. Spegs were detected in the germinal centers, co-located with CD23-positive follicular dendritic cells, and were present in the sinuses. Likewise, lymph nodes with spems and spegs in AE and CE were significantly enlarged in size in comparison to the control group.Conclusions/significancemAb EmG3 is specific for AE and CE and is a valuable tool in the histological diagnosis of echinococcosis. Based on the observed staining patterns, we hypothesize that the interaction between parasite and host is not restricted to the main lesion since spegs are detected in lymph nodes. Moreover, in AE the number of spems-affected lymph nodes is higher than previously assumed. The enlargement of lymph nodes with spems and spegs points to an immunological interaction with the small immunogenic particles (spems and spegs) of Echinococcus spp.

Project description: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 (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.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 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 significanceAE 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.

Project description:Alveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. We recently showed that E. multilocularis metacestode vesicles scavenge large amounts of L-threonine from the culture medium. This motivated us to study the effect of L-threonine on the parasite and how it is metabolized. We established a novel metacestode vesicle growth assay with an automated readout, which showed that L-threonine treatment led to significantly increased parasite growth. In addition, L-threonine increased the formation of novel metacestode vesicles from primary parasite cell cultures in contrast to the non-proteinogenic threonine analog 3-hydroxynorvaline. Tracing of [U-13C]-L-threonine and metabolites in metacestode vesicles and culture medium resulted in the detection of [U-13C]-labeling in aminoacetone and glycine, indicating that L-threonine was metabolized by threonine dehydrogenase (TDH). EmTDH-mediated threonine metabolism in the E. multilocularis metacestode stage was further confirmed by quantitative real-time PCR, which demonstrated high expression of emtdh in in vitro cultured metacestode vesicles and also in metacestode samples obtained from infected animals. EmTDH was enzymatically active in metacestode vesicle extracts. The compounds disulfiram, myricetin, quercetin, sanguinarine, and seven quinazoline carboxamides were evaluated for their ability to inhibit recombinantly expressed EmTDH. The most potent inhibitors, albeit not very strong or highly specific, were disulfiram, myricetin and sanguinarine. These compounds were subsequently tested for activity against E. multilocularis metacestode vesicles and primary parasite cells and only sanguinarine demonstrated significant in vitro activity. However, TDH is not its only cellular target, and it is also known to be highly toxic. Our findings suggest that additional targets of sanguinarine should be explored, and that it may serve as a foundation for developing more specific compounds against the parasite. Moreover, the EmTDH assay could be a valuable high-throughput, target-based platform for discovering novel anti-echinococcal compounds.

Project description:ObjectiveAlveolar echinococcosis (AE) is a zoonosis caused by the larval stage of the metacestode Echinococcosis multilocularis with a tumor-like behavior in the targeted organ, especially in the liver. Surgery with albendazole is first-line modality for AE. Drug discontinuation is usually based upon the parasitic viability shown by the positron emission tomography (PET) scan. However, as a demanding and expensive method, it is not widely practiced in majority of the endemic regions. Further understanding on the cytokine and chemokine response profiles in AE patients may provide an interesting insight for potential markers in viability assessment.MethodsMice were inoculated with Echinococcus multilocularis intrahepatically to develop the hepatic AE murine model. Oral albendazole administration was then applied for three months after the first inoculation, and peripheral and regional immune cells including type 1 T helper cells (Th), Th2, Th17, regulatory T (Treg) cells, related cytokines, and chemokines were examined.ResultsThe hepatic AE lesion was confirmed by ultrasound examination resulting in a successful rate of 70%. Among the 17 cytokines and chemokines detected, plasma levels of IL-23 were significantly higher in E. multilocularis-infected mice when compared to the control group; furthermore, more obvious increasing levels were found after albendazole treatment (p < 0.05). All chemokine levels other than eotaxin and MCP-3 were slightly higher in E. multilocularis-infected mice compared to the control group (p > 0.05). Eotaxin levels were significantly decreased in mice with E. multilocularis infection followed by albendazole treatment (p < 0.05). Both IL-17A and IL-23 expressions in hepatic AE lesions were significantly higher and related with disease activity.ConclusionAlbendazole administration influenced the balance of immune response and promotes the secretion of proinflammatory factors which is beneficial to parasite clearance. IL-23 seems to be associated with the successful albendazole treatment in mice with E. multilocularis infection; such a change could be translated into clinical application in the near future.

Dataset Information

Albendazole increases the inflammatory response and the amount of Em2-positive small particles of Echinococcus multilocularis (spems) in human hepatic alveolar echinococcosis lesions.

Background

Methodology/principal findings

Conclusions/significance

Publications

Albendazole increases the inflammatory response and the amount of Em2-positive small particles of Echinococcus multilocularis (spems) in human hepatic alveolar echinococcosis lesions.

Similar Datasets

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