Youssef Hamway (Munich / DE), Kaspar Zimmermann (Allschwil / CH), Marcel J. J. Blommers (Allschwil / CH), Cécile Häberli (Allschwil / CH), Shashank Kulkarni (Billerica, MA / US), Susanna Skalicky (Vienna / AT), Matthias Hackl (Vienna / AT), Marjo Götte (Allschwil / CH), Jennifer Keiser (Allschwil / CH), Prof. Dr. Clarissa Prazeres da costa (Munich / DE), Dr. Thomas Spangenberg (Darmstadt / DE), Kamal Azzaoui (Allschwil / CH)
Abstract text
Introduction
Schistosoma is a genus of parasitic trematode responsible for causing schistosomiasis, this is perpetuated by an often chronic infection in which the parasite can persist for decades in the host. This persistence suggests a complex interaction where host factors are utilized for parasite development and the parasite modulates the host immune response[1]. One mechanism of immune modulation is through the use of microRNAs present in extracellular vesicles secreted by the parasites to regulate host immune cells. Schistosoma species mansoni, japonicum and hematobium, each produce a number of different microRNAs; with S. mansoni alone producing over 200 of these[2]. sma-miRNA-10 in particular has been shown to influence host T-cell fate determination through manipulation of the NF-κB pathway[3].
Objectives
Our objective was to identify small molecules that can bind Schistosoma miRNA and interfere with this immunomodulation.
Material & methods
We used a fragment-based screening approach by means of NMR to identify binders to the parasite microRNA-10. The small fragments identified were used to make larger elaborated molecules, which were then tested in cellular assays to confirm their ability to interfere with the action of sma-miR-10.
Results
We have identified low molecular weight tool compounds that can interfere with this microRNA-mediated Schistosoma mansoni manipulation of the host immune system. These molecules were demonstrated in cellular assays to counteract NF-κB activity inhibition by S. mansoni miRNA-10.
Conclusions
This work suggests a potential role for such compounds in modulating host-pathogen interactions. More generally, these compounds offer a proof-of-concept as microRNA-targeting small molecules, that yield a distinct phenotype.
[1] Y. Ofir-Birin, N. Regev-Rudzki, Science 2019, 363, 817-818.
[2] L. Zhu, J. Liu, G. Cheng, Front Cell Infect Microbiol 2014, 4, 165-165.
[3] T. Meningher, Y. Barsheshet, Y. Ofir‐Birin, D. Gold, B. Brant, E. Dekel, Y. Sidi, E. Schwartz, N. Regev‐Rudzki, O. Avni, D. Avni, EMBO reports 2020, 21.