Understanding parasitic flatworm biology as key to new drug targets
Dr. Simone Häberlein
Institute of Parasitology, BFS, Justus Liebig University Giessen
Imagine a girl and a boy somewhere in Kenya – they go for swimming with their friends in a nearby lake. This lake is infested with snails shedding infectious larvae of the blood fluke Schistosoma mansoni, a parasitic flatworm infecting these kids and further >200 mio people worldwide. How fast will these kids be infected by the larvae – in seconds or minutes? By which chemical cues does the parasite recognize its victim as host? How does the parasite manipulate the host´s immune system? How does the parasite grow and reproduce within its host? How can we kill the parasite? These questions have been part of my research on S. mansoni.
Using in silico approaches, worm in vitro-culture systems, genomics and post-genomics tools we currently address: (1) the characterization of stem cell-associated genes and (2) of cellular stress responses to identify novel drug targets, (3) screening of innovative compounds, e.g. originating from insects, and (4) translation of results from schistosomes to the related liver fluke Fasciola hepatica, which causes fasciolosis, a foodborne zoonosis affecting humans and livestock worldwide.
In our stem cell project, we focus on transcription factors and RNA-binding proteins directing stem-cell proliferation vs. differentiation. Retinoic-acid signaling and genes such as dmrt1, both well-known from vertebrate development, appear as key regulators also in this invertebrate species. Following differentiation, parasite cells may face a hostile environment, which requires strategies to deal with oxidative stress. To this end, we characterized the schistosome autophagy machinery which serves to degrade unwanted cellular proteins, and aldehyde dehydrogenases (ALDH) which mediate detoxification of harmful cellular aldehydes. Targeting both detox systems with inhibitors affected worm viability in nanomolar to low micromolar concentrations. Next to this target-focused approach, my research focuses on insects as a yet neglected source for the discovery of anthelminthics.
Indeed, a compound from lady beetles affected viability and stem cell proliferation of S. mansoni. Translation of above findings to F. hepatica revealed a promising cross-species activity of some compounds. These attempts demonstrate the power of combining basic biology and applied research aiming at discovering basic principles of parasite cell biology which can be exploited for new strategies to control flukes, but also other helminths.