Project

Discipline

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

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.

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Last update: 01.04.2015

Active participation

Self-organised

Communication	Title	Media	Place	Year

Number	Title	Start	Funding scheme

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.