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Energy-generating pathways of the parasite Echinococcus multilocularis and their potential for novel, targeted treatments against alveolar echinococcosis

English title Energy-generating pathways of the parasite Echinococcus multilocularis and their potential for novel, targeted treatments against alveolar echinococcosis
Applicant Lundström-Stadelmann Britta
Number 192072
Funding scheme Project funding (Div. I-III)
Research institution Institut für Parasitologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Medical Microbiology
Start/End 01.04.2020 - 31.03.2024
Approved amount 700'000.00
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Keywords (8)

chemotherapy; threonine; energy metabolism; malate dismutation; Echinococcus multilocularis; albendazole; threonine dehydrogenase; glucose

Lay Summary (German)

Lead
Die alveoläre Echinokokkose ist eine gravierende parasitäre Erkrankung, welche durch Larven des Fuchsbandwurmes verursacht wird. Es gibt immer mehr Infektionen von Menschen, aber auch Hunden, und anderer Tiere, mit diesem Parasiten (auch in der Schweiz). Dieses Projekt soll das Verständnis der Erkrankung fördern, und zu neuen Therapieansätzen führen.
Lay summary

Inhalt und Ziele des Forschungsprojektes

 

Der Fuchsbandwurm Echinococcus multilocularis verursacht die lebensbedrohliche Erkrankung alveoläre Echinokokkose (AE), welche vornehmlich die Leber befällt. Der Parasit manifestiert sich dort als tumorartig wachsendes Larvenstadium (Metazestode), welches schwere Schädigungen verursacht. Die Medikamente, welche heute gegen die AE eingesetzt werden, dämmen das Wachstum des Parasiten ein, vermögen ihn jedoch nicht abzutöten. Diese Wirkstoffe müssen daher zeitlebens in grösseren Mengen eingenommen werden, was zu starken Nebenwirkungen führen kann. Daher ist es wichtig, die aktuellen Medikamente besser zu verstehen, und neue und verbesserte Therapien zur Heilung der AE zu entwickeln.

Um dies tun zu können, haben wir in der Vergangenheit den Stoffwechsel des Fuchsbandwurms unter die Lupe genommen, und herausgefunden, dass er ungewöhnliche Wege benutzt, um Energie zu generieren. Diese Wege sind noch weitgehend unerforscht, bekannt ist aber, dass der Mensch diese nicht besitzt. Somit wären die speziellen Energiestoffwechselwege des Fuchsbandwurmes ein geeignetes Ziel für neue Therapien. Genau dies wollen wir im vorliegenden Projekt untersuchen und letztlich auch gezielt Hemmstoffe testen.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Die zuvor beschriebenen Studien führen nicht nur zu neuen Erkenntnissen zum Fuchsbandwurm, sondern auch bzgl. anderer parasitischer Würmer wie zB dem Hundebandwurm, dem Rinderbandwurm, und anderer, die weltweit sehr viele Erkrankungen verursachen.
Direct link to Lay Summary Last update: 27.03.2020

Responsible applicant and co-applicants

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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 (Div. I-III)
198127 High-resolution Electron Impact Ionization Mass Spectrometer equipped with a Gas Chromatograph 01.01.2021 R'EQUIP

Abstract

Background and rationale:The metacestode (larval stage) of the helminth Echinococcus multilocularis is the causative agent of alveolar echinococcosis (AE), a severe and in many cases incurable disease in humans. Radical curative surgery is not possible in many AE patients, and therapy based on albendazole (ABZ) or mebendazole is presently the only approved option for a stabilizing, but non-curative, treatment. The mode of action of ABZ in E. multilocularis has not been conclusively elucidated. While tubulin is involved in the efficacy of the drug, several studies point also towards a direct involvement of the energy metabolism of the parasite. Thus, a better understanding of the current treatment and novel therapeutic strategies are needed. Our previous drug-screening approaches against AE point towards the energy metabolism as a highly valuable drug target. Moreover, E. multilocularis depends on nutrients that it scavenges from its host, with glucose and threonine as the most strongly consumed metabolites. Both molecules contribute in the energy metabolism of the parasite, which is, as in comparison to in mammals, different and unexplored, and offers new targetable pathways: Glucose is metabolized through glycolysis, fermentation, citric acid cycle, and electron transfer chain (ETC), and as in other helminths, E. multilocularis can metabolize glucose also via the largely unexplored malate dismutation (MD). The role of the strongly consumed threonine in the energy-generating pathways of the parasite, possibly involving threonine dehydrogenase (TDH), is a novel finding that has not been explored to date. Thus, we need to understand the molecular basis of the glucose and threonine metabolism in the metacestode of E. multilocularis, to then apply these insights to develop novel treatment strategies that synergistically target these energy-generating pathways. Overall objective and specific aims:The overall objective of this project is the development of novel and highly efficacious treatment approaches against AE by targeting energy-generating pathways of E. multilocularis metacestodes. To achieve this goal, the following specific aims will be pursued:-Aim 1: Elucidate the hallmarks of the glucose metabolism of E. multilocularis metacestodes, including the role of ABZ.-Aim 2: Clarify the role and importance of threonine in the energy generating pathways of E. multilocularis.-Aim 3: Develop chemotherapeutical treatments based on targeting several energy-generating pathways of E. multilocularis.Methods:To achieve aim 1 we will address 13C-glucose flux analyses in in vitro cultured E. multilocularis, including effects on MD activity induced by changes in oxygen concentration or by blocking of the ETC. Inhibitors of MD will be identified by drug repurposing, applying our established in vitro screening cascade and specific assays for measurement of MD activity, including effects on the ETC. This will also include the assessment of ABZ as a potential MD inhibitor. Analyses on ABZ will be extended by a non-targeted approach, which is based on identification of drug-binding proteins and overall metabolomic changes in ABZ-treated metacestodes. For aim 2 we will perform 13C-threonine flux analyses and follow-up assays to confirm that threonine is used for energy generation and/or cell proliferation. We will assess the uptake of threonine into parasite cells, study parasite growth induced by threonine, and the effects of threonine on the activity of MD and ETC. The threonine-consuming enzyme TDH from E. multilocularis will be expressed as a functional recombinant protein, and activity assays, immunolocalization, knock-down by RNAi in parasite cells, and specific inhibition with repurposed drugs will be carried out. Active TDH inhibitors will be tested against whole metacestodes in vitro. In aim 3 we will integrate our findings of aims 1 and 2 and target the glucose (MD, ETC) and threonine metabolism (TDH) of E. multilocularis using drug combinations. These tests will be performed in vitro and in the in vivo mouse model. Expected results and impact of the proposed project:Our previous results on the metabolic footprint of E. multilocularis and various drug-screening approaches all point towards the parasite energy metabolism as a highly valuable drug target. In this project, we will focus on elucidating the mechanisms involved in the largely unexplored MD and TDH pathways. This will provide important insights that we will apply to chemically inhibit the parasite’s energy-generating machinery. We will study the effects of ABZ on the energy metabolism of E. multilocularis and thereby better understand the mode of action of the current drug used for treatment of AE. We anticipate that application of a combination of drugs, acting on several pathways, will be efficacious in killing these parasites in a more efficient way than the current treatments. Thus, our studies will provide a scientific basis for the development of novel therapeutic approaches for AE, and could well impact on other diseases inflicted by helminths.
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