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Echinococcus multilocularis and alveolar echinococcosis: immunomodulatory mechanisms as potential target for immuno- and chemotherapeutical intervention

English title Echinococcus multilocularis and alveolar echinococcosis: immunomodulatory mechanisms as potential target for immuno- and chemotherapeutical intervention
Applicant Gottstein Bruno
Number 141039
Funding scheme Project funding
Research institution Institut für Parasitologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Medical Microbiology
Start/End 01.04.2012 - 31.03.2015
Approved amount 627'000.00
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All Disciplines (2)

Discipline
Medical Microbiology
Immunology, Immunopathology

Keywords (8)

alveolar echinococcosis; immunology; Echinococcus multilocularis; immune modulation; experimental immunotherapy; drug target; experimental chemotherapy; RNAi

Lay Summary (English)

Lead
Lay summary

Alveolar echinococcosis (AE) is a severe chronic helminthic disease caused by the intrahepatic tumor-like growth of the metacestode of Echinococcus multilocularis. This parasite has evolved sophisticated strategies to escape host immune responses, mainly by manipulating and directing this immune response towards anergy and/or tolerance. Our research group is trying to better understand this complex parasite-host relationship, and to pinpoint the specific crucial events that lead to disease. We anticipate also a prectical impact of our research, including the development of novel treatment strategies and options. These will include not only immunotherapeutic options, but also novel chemotherapeutic  approaches. In more details, we will study the down-regulated immune status that evolves during chronic murine AE, focusing on the role of regulatory T-cells and the respective cytokine network, with emphasis on TGF-β.   In vitro and in vivo drug screening has lead to the identification of novel potential chemotherapeutical options (mefloquine, artemisinin- and pentamidine-derivatives), and we try to identify corresponding metacestode drug targets by biochemical means and study their function and importance employing cell biological and molecular techniques. We apply an Echinococcus-specific chip-based gene-expression microarray, which we just developed, to carry out stage-specific transcriptome analyses, and we will exploit the recently established RNAi-methodology to assess the functionality of selected proteins and drug targets in E. multilocularis.    Overall, this is an interdisciplinary project, which combines parasitological, immunological, molecular and cell biological and pharmacological studies in order to gain insights on the complex host-parasite relationship during experimental murine AE. 


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Activities of fenbendazole in comparison with albendazole against Echinococcus multilocularis metacestodes in vitro and in a murine infection model
Kuester Tatiana, Stadelmann Britta, Aeschbacher Denise, Hemphill Andrew (2014), Activities of fenbendazole in comparison with albendazole against Echinococcus multilocularis metacestodes in vitro and in a murine infection model, in INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, 43(4), 335-342.
Alveolar Echinococcosis Metabolic Imaging: from In Vitro Testing to Small Animal Positron Emission Tomography
Porot C., Knapp J., Wang J., Camporese D., Germain S., Boulahdour H., Seimbille Y., Gottstein B., Vuitton D. A., Blagosklonov O. (2014), Alveolar Echinococcosis Metabolic Imaging: from In Vitro Testing to Small Animal Positron Emission Tomography, in Engineering in Medicine and Biology Society (EMBC), 2014 36th Annual International Conference of the, Chicago 40, 40.
Amino ozonides exhibit in vitro activity against Echinococcus multilocularis metacestodes
Kuester Tatiana, Kriegel Nadja, Stadelmann Britta, Wang Xiaofang, Dong Yuxiang, Vennerstrom Jonathan L., Keiser Jennifer, Hemphill Andrew (2014), Amino ozonides exhibit in vitro activity against Echinococcus multilocularis metacestodes, in INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, 43(1), 40-46.
Echinococcus metacestode: in search of viability markers
Gottstein Bruno, Wang Junhua, Blagosklonov Oleg, Grenouillet Frederic, Millon Laurence, Vuitton Dominique A., Mueller Norbert (2014), Echinococcus metacestode: in search of viability markers, in PARASITE, 21(63), 1-10.
Echinococcus P29 Antigen: Molecular Characterization and Implication on Post-Surgery Follow-Up of CE Patients Infected with Different Species of the Echinococcus granulosus Complex
Boubaker Ghalia, Gottstein Bruno, Hemphill Andrew, Babba Hamouda, Spiliotis Markus (2014), Echinococcus P29 Antigen: Molecular Characterization and Implication on Post-Surgery Follow-Up of CE Patients Infected with Different Species of the Echinococcus granulosus Complex, in PLOS ONE, 9(5), 1-13.
Evaluation of the Diagnostic Value of the ELISA Tests Developed by Using EgHF, Em2 and EmII/3-10 Antigens in the Serological Diagnosis of Alveolar Echinococcosis
Pektas Bayram, Altintas Nazmiye, Akpolat Nezahat, Gottstein Bruno (2014), Evaluation of the Diagnostic Value of the ELISA Tests Developed by Using EgHF, Em2 and EmII/3-10 Antigens in the Serological Diagnosis of Alveolar Echinococcosis, in MIKROBIYOLOJI BULTENI, 48(3), 461-468.
Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development
Hemer Sarah, Konrad Christian, Spiliotis Markus, Koziol Uriel, Schaack Dominik, Foerster Sabine, Gelmedin Verena, Stadelmann Britta, Dandekar Thomas, Hemphill Andrew, Brehm Klaus (2014), Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development, in BMC BIOLOGY, 12, 1-22.
Immunoblotting for the serodiagnosis of alveolar echinococcosis in alive and dead Eurasian beavers (Castor fiber).
Gottstein B, Frey C F, Campbell-Palmer R, Pizzi R, Barlow A, Hentrich B, Posautz A, Ryser-Degiorgis M-P (2014), Immunoblotting for the serodiagnosis of alveolar echinococcosis in alive and dead Eurasian beavers (Castor fiber)., in Veterinary parasitology, 205(1-2), 113-8.
Profound Activity of the Anti-cancer Drug Bortezomib against Echinococcus multilocularis Metacestodes Identifies the Proteasome as a Novel Drug Target for Cestodes
Stadelmann Britta, Aeschbacher Denise, Huber Cristina, Spiliotis Markus, Mueller Joachim, Hemphill Andrew (2014), Profound Activity of the Anti-cancer Drug Bortezomib against Echinococcus multilocularis Metacestodes Identifies the Proteasome as a Novel Drug Target for Cestodes, in PLOS NEGLECTED TROPICAL DISEASES, 8(12), 1-13.
Transcriptional Profiles of Cytokine/Chemokine Factors of Immune Cell-Homing to the Parasitic Lesions: A Comprehensive One-Year Course Study in the Liver of E. multilocularis-Infected Mice
Wang Junhua, Lin Renyong, Zhang Wenbao, Li Liang, Gottstein Bruno, Blagosklonov Oleg, Lu Guodong, Zhang Chuangshan, Lu Xiaomei, Vuitton Dominique A., Wen Hao (2014), Transcriptional Profiles of Cytokine/Chemokine Factors of Immune Cell-Homing to the Parasitic Lesions: A Comprehensive One-Year Course Study in the Liver of E. multilocularis-Infected Mice, in PLOS ONE, 9(3), 1-15.
Treatment of echinococcosis: albendazole and mebendazole - what else?
Hemphill Andrew, Stadelmann Britta, Rufener Reto, Spiliotis Markus, Boubaker Ghalia, Mueller Joachim, Mueller Norbert, Gorgas Daniela, Gottstein Bruno (2014), Treatment of echinococcosis: albendazole and mebendazole - what else?, in PARASITE, 21(70), 1-9.
A Multiplex PCR for the Simultaneous Detection and Genotyping of the Echinococcus granulosus Complex
Boubaker Ghalia, Macchiaroli Natalia, Prada Laura, Cucher Marcela A., Rosenzvit Mara C., Ziadinov Iskender, Deplazes Peter, Saarma Urmas, Babba Hamouda, Gottstein Bruno, Spiliotis Markus (2013), A Multiplex PCR for the Simultaneous Detection and Genotyping of the Echinococcus granulosus Complex, in PLOS NEGLECTED TROPICAL DISEASES, 7(1), 1-13.
Fatal Alveolar Echinococcosis of the Lumbar Spine
Keutgens Aurore, Simoni Paolo, Detrembleur Nancy, Frippiat Frederic, Giot Jean-Baptiste, Spirlet Francois, Aghazarian Saro, Descy Julie, Meex Cecile, Huynen Pascale, Melin Pierrette, Muller Norbert, Gottstein Bruno, Carlier Yves, Hayette Marie-Pierre (2013), Fatal Alveolar Echinococcosis of the Lumbar Spine, in JOURNAL OF CLINICAL MICROBIOLOGY, 51(2), 688-691.
In Vitro and In Vivo Activities of Dicationic Diguanidino Compounds against Echinococcus multilocularis Metacestodes
Kuester Tatiana, Kriegel Nadja, Boykin David W., Stephens Chad E., Hemphill Andrew (2013), In Vitro and In Vivo Activities of Dicationic Diguanidino Compounds against Echinococcus multilocularis Metacestodes, in ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 57(8), 3829-3835.
Subcutaneous Infection Model Facilitates Treatment Assessment of Secondary Alveolar Echinococcosis in Mice
Kuester Tatiana, Hermann Corina, Hemphill Andrew, Gottstein Bruno, Spiliotis Markus (2013), Subcutaneous Infection Model Facilitates Treatment Assessment of Secondary Alveolar Echinococcosis in Mice, in PLOS NEGLECTED TROPICAL DISEASES, 7(5), 1-5.

Collaboration

Group / person Country
Types of collaboration
Prof. C.R. Largiadèr, Institute of Clinical Chemistry, University of Berne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
IPZ, Prof. P. Deplazes, Universität Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
University Hospital Zürich; Prof. B Mühllhaupt Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Guido Beldi; Universitätsklinik für Viszerale Chirurgie und Medizin Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Unité Mixte de Recherche - Chrono-Environnement (UMR 6249 CNRS), Besançon; Prof. Laurence Millon France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
AG Brehm; Prof. Klaus Brehm, University of Würzburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Service de Médecine Nucléaire CHU Jean MINJOZ; Dr. Oleg Blagosklonov France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. P. Bütikofer, Institut für Biochemie und Molekulare Medizin, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Toronto; Dr. Itay Shalev Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events



Self-organised

Title Date Place

Communication with the public

Communication Title Media Place Year
Media relations: radio, television Echinococcose FranceTVPluzz Refionalnachrichten International 2014

Awards

Title Year
Titre de Professeur Honoraire, Université de Franche-Comté, France 2012

Associated projects

Number Title Start Funding scheme
160108 Search for novel immuno- and chemotherapeutical approaches to treat alveolar echinococcosis 01.04.2015 Project funding
125990 Echinococcus multilocularis and alveolar echinococcosis: the molecular struggle 01.04.2009 Project funding
125990 Echinococcus multilocularis and alveolar echinococcosis: the molecular struggle 01.04.2009 Project funding

Abstract

SUMMARY OF RESEARCH PLANa) Background: Alveolar echinococcosis (AE) is a severe chronic helminthic disease caused by the intrahepatic tumor-like growth of the metacestode of Echinococcus multilocularis. This parasite has evolved sophisticated strategies to escape host immune responses, mainly by manipulating and directing this immune response towards anergy and/or tolerance. Our research group, and others, have revealed a number of respective immunoregulatory mechanisms related to dendritic cell (DC) and T cell activities. The overall objective of the present project is to pursue a better understanding of this complex parasite-host relationship, and to pinpoint the specific crucial events that lead to disease, all targeted towards the development of novel treatment strategies and options. These will include not only immunotherapeutic options, but furthermore also novel chemotherapeutic approaches. b) Working hypothesis and specific aims: Similar to other helminth infections, immuno-suppression and/or -regulation is an important phenomenon also in AE. We first hypothesize that the parasite orchestrates, during early and later infection stages, the development of a rather anergic, compromised immunological situation in the periparasitic environment, making use of regulatory factors that are employed by the host to conventionally antagonize excessive responses. In this context, we will study the down-regulated immune status evolved during chronic murine AE, focusing on the role of regulatory T-cells and the respective cytokine network, with emphasis on TGF-ß. In a similar context, three candidate host key genes that have been found up-regulated in the periparasitic liver tissue of infected mice will be studied in more detail: FGL2, an inhibitor of DC maturation and T cell proliferation; STAT1, which plays a role in inflammatory processes, and MARCO, which may be relevant in the recognition of parasite glycans. On part of the metacestodes, the modulation of the host immune responses is most likely orchestrated by parasite metabolites. Such molecules may also represent important factors in the cellular development of the metacestode itself. In this context, we will carry out studies on a series of metacestode molecules that we selected based upon their putatively high functional significance in metacestode-host interactions. These are P29, an endophilin-like protein and antigen, the two previously described carbohydrate antigens Em2(G11), Em492, and EmPGI. In vitro and in vivo drug screening has lead to the identification of novel potential chemotherapeutical options (mefloquine, artemisinin- and pentamidine-derivatives), and we will identify corresponding metacestode drug targets by biochemical means and study their function and importance employing cell biological and molecular techniques. We will evaluate and apply an Echinococcus-specific chip-based gene-expression microarray, which we just developed to carry out stage-specific transcriptome analyses, and we will exploit the recently established RNAi-methodology to assess the functionality of selected proteins and drug targets in E. multilocularis.c) Experimental design and/or methods: This is an interdisciplinary project, which combines parasitological, immunological, molecular and cell biological and pharmacological studies in order to gain insights on the complex host-parasite relationship during experimental murine AE. The project is linked to a number of cooperations with other research groups, and a series of joint projects that synergistically contribute to carry out experimental steps financially not covered by the SNF-project. Methodically we will apply modern approaches such as the use of gene-specific knock-out mice, novel Echinococcus-specific chip-based gene-expression microarray, affinity chromatography employing matrix-bound drug derivatives, recombinant protein expression, in vitro metacestode and Echinococcus cell culture, and RNAi-approaches.d) Expected value of the proposed project: This project will enhance the insight into the complex biology of the host-parasite relationship as it occurs during both experimental AE (in the murine model), and will provide relevant information on host- and parasite-derived components that define the host-parasite relationship and how it is manipulated by E. multilocularis metacestodes. In addition, we will identify important drug targets for the rational design of interventional approaches such as immuno- and/or chemotherapy.
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