Male-controlled interpretation of host environmental factors conducts the sexual maturation of S. mansoni females

• Applicant: Professor Dr. Christoph G. Grevelding
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561345890

The worm parasite Schistosoma mansoni causes schistosomiasis, an infectious disease with worldwide meaning. Remarkably, the development of the reproductive organs of the female depends on continuous pairing contact with the male. Basis for this phenomenon are molecular communication processes. Their consequences for females are poorly understood. Knowledge about the “inductive” role of males for female-gonad development is in its infancy, although this is relevant for basic research because pairing is the prerequisite for egg production and thus essential for life-cycle maintenance. Furthermore, eggs are responsible for the pathological consequences of schistosomiasis. Based on recent results from our lab, we hypothesize that the sexual maturation (especially the differentiation of mature oocytes) depends on both, the continuous influence of the paired male on gene expression in females, and specific factors of the host environment. Only in this combination, processes in the female such as oocyte differentiation occur. Among these host factors are retinoic acids (RA) as deduced from our identification and characterization of a nuclear receptor of the RA family, SmRAR. SmRAR is developmentally (adult stage), pairing-dependently and ovary-preferentially regulated. RNAi (knock-down, KD) of Smrar resulted in the loss of mature oocytes in paired females – indicative for a meiosis defect. The project covers the following 5 aims. We will 1. Visualize RA uptake in adult S. mansoni in vitro and study the physiological effects of RA. 2. Clone SmRAR and NR-paralogs like RXR genes of S. mansoni for interaction studies (Yeast-2-Hybrid system); and we will functionally characterize these paralogs (RNAi). 3. Establish cell-based reporter gene assays to study RA binding to NRs. 4. Perform the first CRISPR/Cas-based genome editing experiment to knock-out (KO) Smrar. A CRISPR/Cas-editing protocol was recently established by us (and published) starting with in vitro-laid eggs as biological targets for germ-line transformation. RNA-seq-based transcriptomics will follow to study SmRAR- downstream effects. We plan to compare these data with RNA-seq data of the Smrar-RNAi approach – the first comparative KO/KD analysis of this kind worldwide. 5. Conduct first functional analyses (CRISPR/Cas und RNAi) of the thyroid hormone receptor, which is transcribed as Smrar ovary-preferentially in paired females. This suggests that thyroid may serve as further important host factor.

• DFG Programme: Research Grants