Funding tool: Basic research projects
Project-ID: LS12-019
Project start: 01. November 2013
Project end: will follow
Runtime: 36 months / finished
Funding amount: € 244.000,00

Brief summary:

Fascioliasis is a food borne disease caused by the trematode Fasciola hepatica, the giant liver fluke, and can be found worldwide. For a long time it was thought that infections of people occur only occasionally from livestock. but direct transmission (human to human) have been reported. The WHO considers human fascioliasis as a disease of major global public health importance, because several million people worldwide are infected by this trematode. In addition, the infection of animal livestock leads to large financial losses. As vaccinations against this parasite are not available yet, anthelmintic drugs are the treatment of choice for both, animals and people. During the last decades the proportion of flukes resistant to drugs has steadily increased. This project proposes to identify genes of Fasciola hepatica that play a crucial role in the lifecycle and in the development of drug resistance, to characterize the encoded proteins and to screen for ligands which may lead to the design of new anthelmintic therapeutic strategies.
Drug resistance found in Fasciola hepatica can be mediated by various mechanisms: (i) accelerated metabolism of drugs, (ii) mutations in target proteins which eliminate drug sensitivity, (iii) accelerated drug efflux via transmembrane transporters of the family of ABC transporters. The latter mechanism is widespread in nature and is also thought to contribute to a large extent to drug resistance in F. hepatica.. In addition, the fluke lives in the bile duct, i.e., in a rather hostile environment, where it must cope with the detergent properties of bile acids. Members of the ABC transporter family are known to transport bile salts. Accordingly, our working hypothesis assumes that F. hepatica relies on one or several transporters to colonize this niche and survive in it. Up to now only one ABC transporter has been cloned from F.hepatica, but our data show that this is only a partial sequence. In addition, antibodies against human ABC transporters recognize several distinct immunoreactive bands. This supports the conjecture that F. hepatica must have many more ABC transporters. Our working hypothesis posits that these transporters represent interesting drug target in the treatment of fascioliasis. Blockage of these transporters i) may render the flukes susceptible to the toxic actions of bile fluid and ii) overcome drug-resistance.
Accordingly, the aims of this project are to
i) clone and characterize ABC transporters expressed by Fasciola hepatica
ii) identify ABC transporters capable of transporting anthelmintic drugs in F.hepatica
iii) check for ABC transporters involved in the transport of bile salts in F.hepatica
iv) test known and novel ABC transporter blockers for their ability to blunt the transport of anthelmintic drugs and bile salts
v) identify mutations that confer drug resistance

Keywords:
Fasciola hepatica, ABC transporters, drug resistance,