Organ-on-a-chip based platforms for continuous characterization of antischistosomal molecules and generation of genetically modified larvae – MICRO-WORMS

Schistosomes are blood-dwelling parasites causing Schistosomiasis, or Bilharzia, the second most important parasitic disease after malaria. It affects 230 million people and is responsible for about 200 000 deaths per year. The pathology of schistosomiasis is mainly due to eggs in host tissues. These eggs cause the formation of granulomas and elicit inflammatory processes, which affect organ functions and increase the risk of cancer. Praziquantel (PZQ) is the unique drug recommended for the treatment of Schistosomiasis. There is an urgent need to discover new antischistosomal molecules.

Schistosome studies are extremely tedious since experiment on adult worms are difficult outside of their mammal host. In particular, in vitro studies in Petri dish do not allow long-term survival and retention of basic biological functions like mobility and production of mature eggs that can hatch into larvae. This project is the result of a collaboration between V. Senez (LIMMS, IRL 2820) and J. Vicogne (CIIL, UMR 9017 CNRS, U1019 INSERM) and is also supported by a continuing collaboration between V. Senez and Pr. Y. Sakai (University of Tokyo) in the development of Organ-On-a-Chip (OOC) and their instrumentation in BioMEMS. We have already conducted several studies on the development of the 3D model of the target organs, namely the liver, and on that of a microfluidic environment imitating mesenteric veins. We have established the proof of concept that adult worms are able to settle and survive in a microfluidic system with significant egg production. We have finally shown a major effect of PZQ on worm motility and surface adhesion at doses as low as 50 nM, which were not considered as significant or lethal in regular in vitro assays.

Our goal is to design two complementary microfluidic devices that will i) sustainably cultivate in vitro couples of adult worms by preserving their fertility and ii) produce a 3D model of liver in which eggs produced by the adult worms will mature thanks to its immunotolerant property. We will therefore develop a miniaturized reproduction of mesenteric veins to simulate the mass transport (nutrient, oxygen and drugs) between the intestinal capillary system and liver. We will also produce a perfused 3D model of liver tissue in which we will study the influence of different cellular and acellular components on egg maturation and, conversely, the influence of eggs on the response of liver tissue. Within these two microfluidic devices, arrayed in 96-wells format, we will show that we can perform efficient screening for therapeutic molecules both on the adult worm (mesenteric chip) and on the eggs (liver chip). In addition, this innovative and instrumented (electrical biosensor) in vitro model mimicking the environment of the host, we will also generate GFP expressing strains by in situ egg electroporation.

In summary, our goal is to offer the community a highly predictive functional screening tool to identify new molecules against Schistosomiasis. This tool will be also able to generate viable in vitro multicellular larvae from adult worms making possible the generation of transgenic strains. Transgenic worms would be an unprecedented tool for the propagation of strains of worms with compromised phenotypes in infected geographical areas.