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. 2022 Oct 14;8(10):2028-2034.
doi: 10.1021/acsinfecdis.2c00360. Epub 2022 Sep 13.

Modulation of Host-Parasite Interactions with Small Molecules Targeting Schistosoma mansoni microRNAs

Youssef Hamway  1   2 , Kaspar Zimmermann  3 , Marcel J J Blommers  3 , Mariana V Sousa  1   2 , Cécile Häberli  4   5 , Shashank Kulkarni  6 , Susanna Skalicky  7 , Matthias Hackl  7 , Marjo Götte  3 , Jennifer Keiser  4   5 , Clarissa Prazeres da Costa  1   2 , Thomas Spangenberg  8 , Kamal Azzaoui  3
Affiliations

Modulation of Host-Parasite Interactions with Small Molecules Targeting Schistosoma mansoni microRNAs

Youssef Hamway et al. ACS Infect Dis. .

Abstract

Parasites use different strategies of communication with their hosts. One communication channel that has been studied in recent years is the use of vesicle microRNAs to influence the host immune system by trematodes. sma-microRNA-10, secreted from Schistosoma mansoni, has been shown to influence the fate of host T-cells through manipulation of the NF-κB pathway. We have identified low molecular weight tool compounds that can interfere with this microRNA-mediated manipulation of the host immune system. We used a fragment-based screening approach by means of nuclear magnetic resonance (NMR) to identify binders to the precursor of the parasite sma-microRNA-10 present in their extracellular vesicles. The small fragments identified were used to select larger molecules. These molecules were shown to counteract the inhibition of NF-κB activity by sma-microRNA-10 in cell-based assays.

Keywords: FBS; NMR; host−parasite; microRNA; schistosome.

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Conflict of interest statement

The authors declare the following competing financial interest(s): S.K. is an employee of EMD Serono Research and Development Institute, Inc., a business of Merck KGaA, Darmstadt, Germany. T.S. is an employee of Ares Trading S.A., an affiliate of Merck KGaA, Darmstadt, Germany. K.Z., M.J.J.B., M.G., and K.A. are employees of Saverna Therapeutics AG. S.S. and M.H. are employees of TAmiRNA GmbH.

Figures

Figure 1
Figure 1
miRNA biogenesis (left). Cascade used to identify small molecules interacting with pre-miRNA sma-pre-miR-10-5p present in the extracellular vesicles of schistosomes to study the host–parasite interaction. (1) Pre-miRNA construct selected for NMR screening (bulge region indicated by dotted circle). (2) Screening by NMR of the fragment library (768 fragments). (3) Selection of molecules by chemical similarity from the vendor catalog. (4) Screening by NMR of the catalog selected molecules (50 molecules). (5) Test compounds in cellular assays.
Figure 2
Figure 2
2D total correlation spectroscopy (TOCSY) NMR fingerprints of the RNA oligonucleotide containing the target binding site of sma-pre-miR-10. The nucleotide sequence and chemical structures of fragment and compound hits are shown in Figure 1. The observed CSP of the RNA at position C7 and not at positions U10, U11, and C12 indicates that the hits bind to the AC mismatch and not to the loop.
Figure 3
Figure 3
Schematic of the experimental approach. (A) Small molecules bind sma-miR-10 produced by adult Schistosoma mansoni, preventing the sma-miR-10-mediated inhibition of the NF-κB activity level in host T-cells; in the experimental model, this is measured using a Jurkat NF-κB luciferase reporter cell line (B).
Figure 4
Figure 4
Cellular assays to investigate the phenotypic effect of compound trans-1 on sma-miR-10 activity. NF-κB luciferase reporter Jurkat cells were transfected with 0.25 μM duplexed sma-mir-10 using DOTAP (1,2-dioleoyl-3-trimethylammonium-propane) as a liposomal transfection agent or exposed to 5–10 Schistosoma mansoni via a 0.4 μm transwell. These cells and control untreated cells were both treated with the above compounds at the indicated concentrations or with DMSO (20 μL). DOTAP without duplex sma-miR-10 was also added to the DMSO-treated cells with no effect on luciferase expression. Both transfection (A) and worm exposure (B) led to a 50% reduction in luciferase expression, which was restored in a dose-dependent manner by each of the compounds. Additionally, RNA was extracted from cells in the same experiment as in (B), and junb RNA expression was measured using qRT-PCR (C) with a similar recovery as that in the luciferase assay. Mean + SEM. Multiple unpaired t tests: *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001. (A, B) n = 3. (C) n = 2.
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