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Search for novel immuno- and chemotherapeutical approaches to treat alveolar echinococcosis

English title Search for novel immuno- and chemotherapeutical approaches to treat alveolar echinococcosis
Applicant Gottstein Bruno
Number 160108
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 01.04.2015 - 31.03.2018
Approved amount 756'000.00
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All Disciplines (2)

Discipline
Medical Microbiology
Immunology, Immunopathology

Keywords (8)

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

Lay Summary (German)

Lead
Die alveoläre Echinokokkose des Menschen ist eine parasitäre Krankheit, welche durch das Larvenstadium des kleinen Fuchsbandwurmes Echinococcus multilocularis verursacht wird. Infolge der zunehmende Verbreitung des Parasiten in Mitteleuropa und in der Schweiz treten jedes Jahr mehr Fälle beim Menschen auf. Das Projekt soll einen wesentlichen Beitrag zur Verbesserung der Therapie dieser Infektionskrankheit leisten.
Lay summary

Die Erkrankung wird durch das tumorartig wachsende Parasitengewebe verursacht. Eine vollständige Heilung der alveolären Echinokokkose ist selten und nur bei radikaler Chirurgie möglich. Alle anderen Fälle werden mittels Dauertherapie mit Albendazol behandelt, dies über Jahre bis Jahrzehnte. Der Parasit dabei in der Regel nicht abgetötet, sondern nur an seinem Weiterwachsen gehindert.

In einem vorgängigen Projekt zeigten wir auf, wie es dem Parasiten gelingt, trotz Immunantwort des Wirtes zu überleben. Dies geschieht durch Aktivierung sogenannter regulatorischer T-Zellen sowie dazugehörender Botenstoffe wie z.B. das TGF-β, welches die Immunantwort des Patienten auf die Infektion schwächt. Ziel des laufenden Forschungsprojektes ist nun, diese immunschwächenden Prozesse genauer zu identifizieren und anschliessend therapeutisch zu neutralisieren, so dass das Immunsystem des Patienten wieder funktionstüchtig gerichtet werden kann.

Parallel zu diesen immunologischen Entwicklungen suchen wir nach Medikamenten mit verbesserter Wirksamkeit bei der AE, d.h. nach solchen, welche den Parasiten abtöten können. Als optimalsten Therapieansatz werden wir Immuntherapie plus Chemotherapie kombinieren, um so die besten Heilungschancen anbieten zu können.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojektes

Die alveoläre Echinokokkose des Menschen ist zwar therapierbar, aber nicht heilbar. Die Krankheit verursacht ca. 100’000 CHF Kosten pro Patient. Die antizipierte Entwicklung einer kurativen Therapie würde diese Krankheitskosten drastisch senken können, sowie auch den Patienten von seiner chronischen Krankheit befreien.

 

Direct link to Lay Summary Last update: 01.04.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Vertebral alveolar echinococcosis-a case report, systematic analysis, and review of the literature.
Meinel Thomas Raphael, Gottstein Bruno, Geib Vanessa, Keel Marius Johann, Biral Ruggero, Mohaupt Markus, Brügger Jan (2018), Vertebral alveolar echinococcosis-a case report, systematic analysis, and review of the literature., in The Lancet. Infectious diseases, 18(3), 87-98.
Screening of antigenic vesicular fluid proteins of Echinococcus multilocularis as potential viability biomarkers to monitor drug response in alveolar echinococcosis patients
Valot Benoit, Rognon Benedicte, Prenel Anais, Baraquin Alice, Knapp Jenny, Anelli Mathilde, Richou Carine, Bresson-Hadni Solange, Grenouillet Frederic, Wang Junhua, Vuitton Dominique Angele, Gottstein Bruno, Millon Laurence (2017), Screening of antigenic vesicular fluid proteins of Echinococcus multilocularis as potential viability biomarkers to monitor drug response in alveolar echinococcosis patients, in PROTEOMICS CLINICAL APPLICATIONS, 11(11-12), 1-12.
Larval Echinococcus multilocularis infection reduces dextran sulphate sodium-induced colitis in mice by attenuating T helper type 1/type 17-mediated immune reactions.
Wang Junhua, Goepfert Christine, Mueller Norbert, Piersigilli Alessandra, Lin Renyong, Wen Hao, Vuitton Dominique A, Vuitton Lucine, Mueller Christoph, Gottstein Bruno (2017), Larval Echinococcus multilocularis infection reduces dextran sulphate sodium-induced colitis in mice by attenuating T helper type 1/type 17-mediated immune reactions., in Immunology, 1-13.
EWET: Data collection and interface for the genetic analysis of Echinococcus multilocularis based on EmsB microsatellite
Knapp Jenny, Damy Sylvie, Brillaud Jonathan, Tissot Jean-Daniel, Navion Jeremy, Melior Raphael, Afonsol Eve, Hormaz Vanessa, Gottstein Bruno, Umhang Gerald, Casulli Adriano, Dadeau Frederic, Millon Laurence, Raoul Francis (2017), EWET: Data collection and interface for the genetic analysis of Echinococcus multilocularis based on EmsB microsatellite, in PLOS ONE, 12(10), 1-14.
Public Health Follow-up of Suspected Exposure to Echinococcus multilocularis in Southwestern Ontario
Trotz-Williams L. A., Mercer N. J., Walters J. M., Wallace D., Gottstein B., Osterman-Lind E., Boggild A. K., Peregrine A. S. (2017), Public Health Follow-up of Suspected Exposure to Echinococcus multilocularis in Southwestern Ontario, in ZOONOSES AND PUBLIC HEALTH, 64(6), 460-467.
To see or not to see: non-invasive imaging for improved readout of drug treatment trials in the murine model of secondary alveolar echinococcosis
Gorgas D., Marreros N., Rufener R., Hemphill A., Lundstroem-Stadelmann B. (2017), To see or not to see: non-invasive imaging for improved readout of drug treatment trials in the murine model of secondary alveolar echinococcosis, in PARASITOLOGY, 144(7), 937-944.
Development of a movement-based in vitro screening assay for the identification of new anti-cestodal compounds
Ritler Dominic, Rufener Reto, Sager Heinz, Bouvier Jacques, Hemphill Andrew, Lundstrom-Stadelmann Britta (2017), Development of a movement-based in vitro screening assay for the identification of new anti-cestodal compounds, in PLOS NEGLECTED TROPICAL DISEASES, 11(5), 1-23.
Molecular characterization of Echinococcus granulosus isolates from Bulgarian human cystic echinococcosis patients
Marinova Irina, Spiliotis Markus, Wang Junhua, Muhtarov Marin, Chaligiannis Ilias, Sotiraki Smaro, Rainova Iskra, Gottstein Bruno, Boubaker Ghalia (2017), Molecular characterization of Echinococcus granulosus isolates from Bulgarian human cystic echinococcosis patients, in PARASITOLOGY RESEARCH, 116(3), 1043-1054.
Immunization of rhesus macaques with Echinococcus multilocularis recombinant 14-3-3 antigen leads to specific antibody response
Lampe Karen, Gottstein B., Becker T., Stahl-Hennig C., Kaup F. -J., Maetz-Rensing K. (2017), Immunization of rhesus macaques with Echinococcus multilocularis recombinant 14-3-3 antigen leads to specific antibody response, in PARASITOLOGY RESEARCH, 116(1), 435-439.
Repeated Long-Term DT Application in the DEREG Mouse Induces a Neutralizing Anti-DT Antibody Response
Wang Junhua, Siffert Myriam, Spiliotis Markus, Gottstein Bruno (2016), Repeated Long-Term DT Application in the DEREG Mouse Induces a Neutralizing Anti-DT Antibody Response, in JOURNAL OF IMMUNOLOGY RESEARCH, 2016(1), 1-5.
Comparison of ex vivo harvested and in vitro cultured materials from Echinococcus granulosus by measuring expression levels of five genes putatively involved in the development and maturation of adult worms
Dezaki Ebrahim Saedi, Yaghoubi Mohammad Mehdi, Spiliotis Markus, Boubaker Ghalia, Taheri Elham, Almani Pooya Ghaseminejad, Tohidi Farideh, Harandi Majid Fasihi, Gottstein Bruno (2016), Comparison of ex vivo harvested and in vitro cultured materials from Echinococcus granulosus by measuring expression levels of five genes putatively involved in the development and maturation of adult worms, in PARASITOLOGY RESEARCH, 115(11), 4405-4416.
Differential Expression of Hox and Notch Genes in Larval and Adult Stages of Echinococcus granulosus
Dezaki Ebrahim Saedi, Yaghoobi Mohammad Mehdi, Taheri Elham, Almani Pooya Ghaseminejad, Tohidi Farideh, Gottstein Bruno, Harandi Majid Fasihi (2016), Differential Expression of Hox and Notch Genes in Larval and Adult Stages of Echinococcus granulosus, in KOREAN JOURNAL OF PARASITOLOGY, 54(5), 653-658.
Triggering and modulation of the host-parasite interplay by Echinococcus multilocularis (vol 137, pg 557, 2010)
Mejri Naceur, Hemphill Andrew, Gottstein Bruno (2016), Triggering and modulation of the host-parasite interplay by Echinococcus multilocularis (vol 137, pg 557, 2010), in PARASITOLOGY, 143(12), 1681-1681.
A dual PCR-based sequencing approach for the identification and discrimination of Echinococcus and Taenia taxa
Boubaker Ghalia, Marinova Irina, Gori Francesca, Hizem Amani, Mueller Norbert, Casulli Adriano, Jerez Puebla Luis Enrique, Babba Hamouda, Gottstein Bruno, Spiliotis Markus (2016), A dual PCR-based sequencing approach for the identification and discrimination of Echinococcus and Taenia taxa, in MOLECULAR AND CELLULAR PROBES, 30(4), 211-217.
Immunoregulation in larval Echinococcus multilocularis infection
Wang J., Gottstein B. (2016), Immunoregulation in larval Echinococcus multilocularis infection, in PARASITE IMMUNOLOGY, 38(3), 182-192.
Screening of the Open Source Malaria Box Reveals an Early Lead Compound for the Treatment of Alveolar Echinococcosis
Stadelmann Britta, Rufener Reto, Aeschbacher Denise, Spiliotis Markus, Gottstein Bruno, Hemphill Andrew (2016), Screening of the Open Source Malaria Box Reveals an Early Lead Compound for the Treatment of Alveolar Echinococcosis, in PLOS NEGLECTED TROPICAL DISEASES, 10(3), 1-19.
Oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine that potentially interacts with parasite ferritin and cystatin
Kuster Tatiana, Stadelmann Britta, Rufener Reto, Risch Corina, Muller Joachim, Hemphill Andrew (2015), Oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine that potentially interacts with parasite ferritin and cystatin, in INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, 46(5), 546-551.
Echinococcus granulosus infection dynamics in livestock of Greece
Chaligiannis I., Maillard S., Boubaker G., Spiliotis M., Saratsis A., Gottstein B., Sotiraki S. (2015), Echinococcus granulosus infection dynamics in livestock of Greece, in ACTA TROPICA, 150, 64-70.
Alveolar and cystic echinococcosis in Europe: Old burdens and new challenges
Deplazes Peter, Gottstein Bruno, Junghanss Thomas (2015), Alveolar and cystic echinococcosis in Europe: Old burdens and new challenges, in VETERINARY PARASITOLOGY, 213(3-4), 73-75.
Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis)
Gottstein Bruno, Wang Junhua, Boubaker Ghalia, Marinova Irina, Spiliotis Markus, Mueller Norbert, Hemphill Andrew (2015), Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis), in VETERINARY PARASITOLOGY, 213(3-4), 103-109.
Taxonomy, phylogeny and molecular epidemiology of Echinococcus multilocularis: From fundamental knowledge to health ecology
Knapp Jenny, Gottstein Bruno, Saarma Urmas, Millon Laurence (2015), Taxonomy, phylogeny and molecular epidemiology of Echinococcus multilocularis: From fundamental knowledge to health ecology, in VETERINARY PARASITOLOGY, 213(3-4), 85-91.
Threat of alveolar echinococcosis to public health - a challenge for Europe
Gottstein Bruno, Stojkovic Marija, Vuitton Dominique A., Millon Laurence, Marcinkute Audrone, Deplazes Peter (2015), Threat of alveolar echinococcosis to public health - a challenge for Europe, in TRENDS IN PARASITOLOGY, 31(9), 407-412.
Prevention and Immunotherapy of Secondary Murine Alveolar Echinococcosis Employing Recombinant EmP29 Antigen
Boubaker Ghalia, Hemphill Andrew, Huber Cristina Olivia, Spiliotis Markus, Babba Hamouda, Gottstein Bruno (2015), Prevention and Immunotherapy of Secondary Murine Alveolar Echinococcosis Employing Recombinant EmP29 Antigen, in PLOS NEGLECTED TROPICAL DISEASES, 9(6), 1-22.
Deletion of Fibrinogen-like Protein 2 (FGL-2), a Novel CD4(+) CD25(+) Treg Effector Molecule, Leads to Improved Control of Echinococcus multilocularis Infection in Mice
Wang Junhua, Vuitton Dominique A., Mueller Norbert, Hemphill Andrew, Spiliotis Markus, Blagosklonov Oleg, Grandgirard Denis, Leib Stephen L., Shalev Itay, Levy Gary, Lu Xiaomei, Lin Renyong, Wen Hao, Gottstein Bruno (2015), Deletion of Fibrinogen-like Protein 2 (FGL-2), a Novel CD4(+) CD25(+) Treg Effector Molecule, Leads to Improved Control of Echinococcus multilocularis Infection in Mice, in PLOS NEGLECTED TROPICAL DISEASES, 9(5), 1-20.
Deletion of fibrinogen-like protein 2, a novel CD4(+) CD25(+) Treg effector molecule, leads to improved control of Echinococcus mutilocularis infection
Lin Renyong, Wang Junhua, Vuitton Dominique, Muller Norbert, Blagosklonov Oleg, Grandgirard Denis, Leib Stephen, Shalev Itay, Levy Gary, Lu Xiaomei, Spiliotis Markus, Wen Hao, Gottstein Bruno (2015), Deletion of fibrinogen-like protein 2, a novel CD4(+) CD25(+) Treg effector molecule, leads to improved control of Echinococcus mutilocularis infection, in JOURNAL OF IMMUNOLOGY, 194, 1-20.

Collaboration

Group / person Country
Types of collaboration
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
- Exchange of personnel
Department for Biomedical Research Universität Bern; Dr. M. Heller Switzerland (Europe)
- Research Infrastructure
University Hospital Zürich; Prof. B Mühllhaupt Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institut für Tropenmedizin, Tübingen; Prof. Peter Soboslay Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
AG Brehm; Prof. Klaus Brehm, University of Würzburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Elanco Animal Health; PD Dr. Heinz Sager Switzerland (Europe)
- Publication
- Industry/business/other use-inspired collaboration
Universitätsklinikum Ulm; Dr. Beate Grüner Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
IPZ, Prof. P. Deplazes, Universität Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Division of Experimental Pathology; Prof. Chr. Mueller Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Imperial College London; Dr. Jia Li Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Gastroenterologie, Inselspital Bern; Prof. Guido Beldi Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Laboratoire de la rage et de la faune sauvage (Dr. Frank Boué); Anses France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Type-2 Immunity Meeting Poster Larval E. multilocularis infection reduces Dextran Sulfate Sodium (DSS)-induced colitis in mice by attenuating Th1/Th2 responses 15.12.2017 Bern, Switzerland Gottstein Bruno; Wang Junhua;
XVII World Congress on Echinococcosis Talk given at a conference Immunomodulation in AE and CE 04.10.2017 Alger, Algeria Wang Junhua; Rufener Reto; Gottstein Bruno; Ritler Dominic; Hemphill Andrew; Lundström-Stadelmann Britta;
Annual meeting of the Swiss Society of Tropical Medicine and Parasitology Poster Experimental Chemotherapy of echinococcosis 30.08.2017 Basel, Switzerland Hemphill Andrew; Ritler Dominic; Gottstein Bruno; Boubaker Ghalia; Wang Junhua; Lundström-Stadelmann Britta; Rufener Reto;
RICAI Paris Talk given at a conference Immunologie et physiopathologie de l'échinococcose alvéolaire 12.12.2016 Palais des Congrès, Paris, France Gottstein Bruno;
EMOP XII Talk given at a conference FoxP3+ regulatory T cells as key parameter in the immunomodulated host response to Echinococcus multilocularis infection 20.07.2016 Turku, Finland Gottstein Bruno; Wang Junhua;
Type-2 Immunity Meeting Talk given at a conference Does fibrinogen-like protein 2 (FGL-2), a novel CD4+ CD25+ Treg effector molecule, contribute to Th2-orientation during chronic alveolar echinococcosis 02.12.2015 Inselspital Bern, Switzerland Gottstein Bruno; Wang Junhua;
THE XXVI-th WORLD CONGRESS ON ECHINOCOCCOSIS Talk given at a conference Epidemiology and control of AE in European countries 01.10.2015 Bucarest, Romania Wang Junhua; Gottstein Bruno;


Self-organised

Title Date Place
Swiss Echino-Meeting 16.09.2016 Haus der Universität, Bern, Switzerland
Treatment and follow-up of AE in human patients 11.02.2016 University of Bern, Switzerland
EurEchino-Registry Workshop 09.04.2015 UFR Science et Technique, Besançon, France

Communication with the public

Communication Title Media Place Year
Media relations: radio, television Echinocoque:le parasite est dans les prés 36.9 (RTS) Western Switzerland 2017

Associated projects

Number Title Start Funding scheme
179439 Targeting the metabolism of Echinococcus multilocularis for the development of novel drug treatments and immunotherapeutic tools 01.04.2018 Project funding
141039 Echinococcus multilocularis and alveolar echinococcosis: immunomodulatory mechanisms as potential target for immuno- and chemotherapeutical intervention 01.04.2012 Project funding

Abstract

SUMMARY OF RESEARCH PLAN a) Background: Alveolar echinococcosis (AE) is one of the clinically most severe zoonotic helminthic diseases in humans, characterized by a chronic progressive hepatic damage caused by the continuous proliferation of the larval stage (metacestode) of Echinococcus multilocularis. The proliferative potential of the parasite metacestode tissue is dependent on the nature/function of the periparasitic immune-mediated processes of the host. Immune tolerance and/or down-regulation of immunity are a marked characteristic increasingly observed at the chronic (late) stage of infection in both humans and in ex¬perimentally infected mice. In this context, explorative studies have clearly shown that T regulatory (Treg) cells play an important role in modulating and orchestrating inflammatory/immune reactions in AE, yielding a largely Th2-biased response, and finally allowing thus long-term parasite survival, prolif¬eration and maturation. b) Working hypothesis and specific aims: We hypothesize that metacestodes secrete immunomod¬ulatory metabolites into the periparasitic environment, and thus create a rather anergic, compromised immunological situation. The parasite makes use of regulatory factors that are employed by Tregs to conventionally antagonize excessive immune responses. Our objectives are (i) to elucidate the respec¬tive cytokine network in detail to define how the expression of these regulatory factors is controlled, and to characterize parameters that could be exploited for the development of novel immunotherapeutic approaches; (ii) to assess the (putatively beneficial) influence of E. multilocularis infection, and conse¬quently of parasite secretory immunomodulatory metabolites, on the course of auto-immune disease (as exemplified in an inducible colitis model); and (iii) to validate recently identified drug targets, and to perform proof-of-concept studies in mice to demonstrate the feasibility, and possibly increased efficacy, of combined immuno- and chemotherapeutical approaches to achieve cure of AE in affected patients. c) Experimental design and/or methods: We have earlier shown that fibrinogen-like protein 2 (FGL2) produced by Tregs plays a major role in the immunomodulatory events that characterize AE. We will explore the effects of in vivo FGL2 neutralization in mice using monoclonal antibodies, and will assess the role of FGL2 in human patients by serological analysis of defined patient groups. The role of Treg cells will be analyzed in more detail using the DEREG mouse model that allows in vivo depletion of Tregs at defined time points during infection, and we will define the factors that account for the down¬regulation / modulation of periparasitic immunity. The regulation of Foxp3 expression, the master reg¬ulator of Treg differentiation, and the role of epigenetic factors (such as long non-coding RNAs that mediate DNA- or histone-methylation) in coordinating Foxp3 expression will be analyzed. In addition, we will investigate the influence of parasite infection on the pathology and immunoregulation in an in¬ducible mouse colitis model for intestinal bowel disease (IBD). In order to develop novel therapeutical treatment options for AE we will, as a first priority, perform a detailed characteriza¬tion of the Echinococcus proteasome by in silico analysis of its constituents, validation by RNAi, purifi¬cation of proteasomes and functional assays, and immunolocalization and expression analysis of defined constituents during infection and treatment). As second priority, we will investigate two other interesting potential drug targets, ferritin and calmodulin. d) Expected value of the proposed project: This project is a logical follow-up of earlier findings on the immunomodulatory properties of E. multilocularis metacestodes. The identification of parasite fac¬tors that interfere in the immune response (such as EmP29, EmG11, Em492 and others), and the novel insights on the importance of Tregs and FGL2 in orchestrating immunological events during AE in favor of the parasite, in combination with the notion that novel and interesting drugs and drug targets are being validated, has now opened the door for a more targeted therapeutic approach. This approach aims to combine immunotherapy with existing, and novel, chemotherapeutical tools.
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