Johanna Ertl (Munich / DE), Dr.rer.nat Fabien Ulrich Prodjinotho (Munich / DE), Youssef Hamway (Munich / DE), Dr. Simone Häberlein (Gießen / DE), Prof. Christoph G. Grevelding (Gießen / DE), Dr. Martin Haselbeck (Munich / DE), Prof. Dr. Clarissa Prazeres da costa (Munich / DE)
Abstract text
Praziquantel (PZQ) is the drug of choice for the treatment and transmission control of schistosomiasis, the most important so-called neglected tropical disease (NTD). PZQ solely targets the adult worms but is ineffective on early migrating larval stages and, thus, does not protect from reinfection. The widespread use of PZQ favors the risk of the development and spread of drug resistance. There is a need to develop novel drugs effective against immature, juvenile, and adult worm stages. We have recently demonstrated the presence of not yet identified soluble multi-stage schistosomicidal factors in the serum of mice, the most widely used experimental laboratory host. The present study aimed to build on these findings to identify the active compound(s) in mouse serum and characterize the anti-schistosome properties.
We used large-scale fractionation of mouse serum to investigate the susceptibility of all schistosome stages in our novel in vitro culture platform that supports long-term larval survival and development. Subsequent comparative mass spectrometry analysis revealed a set of candidates we selected based on enzymatic properties and screened for their multi-stage schistosomicidal efficacy. The hit compound mode of action was defined via confocal microscopy.
Through in vitro screening, we observed that a phospholipase which we named Component X shared a similar schistosome-killing phenotype with mouse serum. Component X lethally affected parasites at all stages, including ex vivo adult worms, in a concentration- and time-dependent manner and is upregulated in infected animals compared to controls. Moreover, the treatment with sublethal doses of Component X affected tegument integrity and disrupted lipid layers and the structure of the parasite"s reproductive system.
Overall, our data reveal that Component X represents a multi-stage schistosomicidal host component, essentially produced in response to infection which could potentially be explored further for the development of novel therapeutic strategies.