Genetics, epigenetics and transcriptomics of schistosome chronobiology – CHRONOGET

Understanding the factors that influence parasite transmission is of central interest to both the public health and evolutionary biology research community. The central aim of this proposal is to identify the genetic, epigenetic and transcriptomic basics of the timing of cercarial shedding pattern in Schistosoma mansoni, a parasitic fluke that infects 67 million people in South America, Middle-East and Africa. This approach is both ambitious and innovative in the field of parasitology; it will focus on the cercarial shedding of the parasite which constitutes the most important life-trait for schistosome transmission to humans. Our project will be the first using the multifaceted contribution of the three "omics", genomics, epigenomics and transcriptomics, in order to analyze the basics of the timing of cercarial shedding in schistosomes, the agents of the second most important parasitic disease in the world after malaria in terms of public health and economic impact.
The life cycle of schistosomes includes a snail host in which schistosome larvae multiplicate clonally and hundreds to thousands of motile cercariae larvae are released into the water where they infect humans or rodents. The timing of cercarial release from the snail varies among populations and overlaps with the activity patterns of their vertebrate hosts. Most S. mansoni populations that primarily infect humans shed cercariae larvae in late morning, while parasite populations that primarily infect rodents shed cercariae in late afternoon or night.
Schistosome parasites are unusual among parasites of humans because they are gonochoric, so genetic crosses can be staged, and the complete lifecycle can be easily maintained in the laboratory. The complete genome sequence and the growing molecular tool kit now allows genomic, epigenomic and functional characterizations. Our project is developed according to three aims.
Aim 1 will use linkage mapping to identify the genome regions and candidate genes underlying cercarial shedding rhythms. We have already completed the cross between nocturnally and diurnally shedding parasites from Oman and identified a genome region on chr. 1 that determines this trait. Field missions will permit to collect natural samples of diurnal/nocturnal shedding chronotypes in order to validate our experimental results.
Aim 2 will use epigenomic tools to identify the genome regions and candidate genes all along the circadian rhythm of cercarial shedding. We have already found a difference between acetylation for two histone H3 amino acid positions, H3K9 and H3K14 in 107 genomic regions for the nocturnally shedding Omanese strain between the hour of the shedding peak and a period with no shedding.
Aim 3 will use RNAseq to examine rhythms in expression of nocturnal and diurnal shedding parasites from Oman across 12 hr light-12 hr dark cycles, to investigate the metabolic pathways underlying control of cercarial release.

While this project aims to answer fundamental questions about parasite biology, there may also be implications for parasite control using interventions against S. mansoni in the snail host parasite. We note that targeted genetic interventions that aim to make vectors refractory to pathogen infection are a rapidly developing approach to control of mosquito borne diseases. Improved understanding of the pathways involved in cercarial release and the interactions between snail and parasite could make this approach feasible for disrupting schistosome transmission from the snail host. This project may have a high public health impact on the transmission control of schistosomiasis both in high and low endemic countries and even in countries where schistosomiasis is emergent, as recently shown by us in France (Corsica). This project fits very well in the "Vie, Santé, bien être" challenge of the ANR and SNR.