Group Lundström-Stadelmann

Host-pathogen interactions and drug treatment

The pathogen

Within our group we focus on the cestode parasite Echinococcus multilocularis, the fox tapeworm, as a model for multicellular pathogens. E. multilocularis grows like a malignant tumor in its intermediate hosts (mainly rodents, but accidentally also dogs, humans, primates, etc) and thereby causes the disease alveolar echinococcosis (AE). If not treated, parasite growth of this most deadly of all helminth infections leads unequivocally to death of the patient.

Novel treatment options against alveolar echinococcosis

Background:
The only curative treatment for AE is surgical resection of the parasite tissue. Surgery is done in about 30% of all AE patients, while most receive chemotherapy only, based solely on the benzimidazole-derivatives mebendazole and albendazole. The present benzimidazole-based chemotherapy cannot kill the parasite (in particular its stem cells) and therefore has to be taken life-long to avoid parasite regrowth. About 16 % of the treated patients experience adverse effects such as hepatotoxicity that lead to treatment discontinuation. With increasing numbers of patients and no alternative to benzimidazoles developed so far, it is important to develop better treatment options.

Our aims:
Based on the in vitro culture of E. multilocularis and specific mouse models, we have developed a number of drug screening assays that allow us to assess larger panels of compounds for activity against E. multilocularis. We are aiming to identify substances that, in contrast to the current therapy, act parasiticidal, thus are killing also the stem cells of the parasite. We study already existing drugs or compound classes from other research areas that could be repurposed for the treatment of AE.

We focus on inhibitors of the parasite's mitochondrial energy metabolism. In a recent publication, we could show that Echinococcus applies more than one way to generate energy in its mitochondira, and that these pathways have to be inhibited simultaneously for a treatment to be effective. Dual inhibition of the Echinococcus multilocularis energy metabolism
In addition, we want to understand the mechanisms of how certain drugs act on the parasite as for example for the drug mefloquine, which was highly active in vitro and in our mouse models of AE: Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis und Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis.

We also test and investigate the efficacy of natural products against the fox tapeworm. Maca against Echinococcosis?-A Reverse Approach from Patient to In Vitro Testing

Efficacious drugs are further tested in AE mouse models and against the closely related E. granulosus, the dog tapeworm, causative agent of cystic echinococcosis (CE). Also CE is a neglected disease, even though it is found roughly ten times more often than AE, and it is not only relevant in humans, but also in animals such as cattle and sheep. As shown in "Establishment and application of unbiased in vitro drug screening assays for the identification of compounds against Echinococcus granulosus sensu stricto" we have established respective in vitro models and can now test substances against the dog tapeworm too.

More information can be found in the following article:
The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis

Starving deadly pathogens: the metabolism of the cestodes parasite Echinococcus multilocularis

Background:
For many pathogens it is yet not completely clear why and how they cause disease and therapies are often based on broad-spectrum anti-infective drugs rather than on species-specific compounds. Importantly, infectious organisms are dependent on their hosts and the nutrients provided by them. By consumption of host nutrients and metabolites, pathogens can damage their host (and cause pathogenicity) and this in turn induces changes in the host cell and pathogen metabolism. This is highly interesting with the thought of developing new therapies against pathogens, namely by starving them of essential metabolites.

Our aims:
To develop novel therapeutic options against infections with E. multilocularis and other helminths, we study the metabolic changes at the host-pathogen interface based on metabolomic and proteomic approaches. This will allow us to study the effects metabolite/protein release/consumption of the parasite has on host cells. Furthermore, the identification of crucial small metabolites and proteins that are released/consumed by E. multilocularis could open up new avenues for the development of alternative or supplementary treatment strategies.

In our publication"In vitro metabolomic footprint of the Echinococcus multilocularis metacestode" we show which metabolites are released and consumed by the parasite. These metabolic pathways could be used as future targets for novel treatments, and are currently under investigation. They include the threonine metabolism and the malate dismutation, a mitochondrial pathway that allows helminths to produce energy when no oxygen is available.

We identified the proteins that build up the parasite and are released by it. This includes one highly interesting molecule, which might be involved in reuptake of nutrients. In our publication "Targeted and non-targeted proteomics to characterize the parasite proteins of Echinococcus multilocularis metacestodes" we show that this molecule is released in high amounts by the parasite, and that it is also taken up by the parasite again. This could offer novel ways of treatment in the future.

We also study general physiological and immunological effects of AE. The host immune response is important in fighting the parasite, and the drugs currently in use against AE can only act if supported by the host immune system. This we showed in the following study: "Short communication: Efficacy of albendazole in Echinococcus multilocularis-infected mice depends on the functional immunity of the host"