Rapamycin impairs viability and reshapes autophagy gene expression in Schistosoma mansoni

Schistosomiasis, caused by blood flukes of the genus Schistosoma, affects millions of people worldwide and leads to substantial morbidity and economic losses. Yet treatment relies almost exclusively on praziquantel, and the possible emergence of parasite strains with reduced sensitivity to the drug, alongside its limited efficacy against pre-patent infections, has highlighted the need for new multi-stage therapeutic approaches. A study from researchers at Instituto Butantan and the University of São Paulo, published in Frontiers in Parasitology, examines whether classical autophagy-modulating compounds can serve as candidate antischistosomal agents and as molecular tools for probing the biology of Schistosoma mansoni.

The research team tested rapamycin, a classical inducer of autophagy, against two developmental stages of the parasite: schistosomula and adult worms. In schistosomula, viability was assessed through total ATP quantification and propidium iodide and fluorescein diacetate assays. In adult worms, the evaluation combined ATP quantification with additional phenotypic measurements, including worm pairing, adhesion to culture plates, motility, and egg production.

The results showed that rapamycin reduced the viability of both stages, with a half-maximal inhibitory concentration of 14.9 micromolar in schistosomula and a lower value of 4.6 micromolar in adult worms, indicating greater potency against the mature parasites. Rapamycin also modulated the expression of several autophagy genes in both parasite stages, measured by reverse transcription quantitative PCR.

Of particular interest, a putative orthologue of TOR, carrying the gene identifier Smp_122910.1, was downregulated in both male and female adult worms exposed to a sublethal dose of rapamycin. The authors report that this stage-specific modulation marks the putative TOR orthologue as a drug-responsive gene candidate for further functional assays.

The study did not stop at rapamycin. The researchers also tested four compounds commonly used to inhibit autophagy in other organisms: bafilomycin A1, chloroquine, spautin-1, and wortmannin. In schistosomula, each compound was evaluated by ATP quantification, and their effects on autophagy gene expression were measured by RT-qPCR in both schistosomula and adult worms.

An instructive asymmetry emerged. Although none of the four inhibitors altered ATP levels in schistosomula, chloroquine did modulate autophagy gene expression in the parasite. This dissociation between the metabolic viability readout and the transcriptional response indicates that autophagy gene expression in S. mansoni is pharmacologically responsive even when ATP levels are not measurably changed under these conditions.

Among the genes whose expression was altered across developmental stages, the authors highlight Lysosome-associated membrane glycoprotein, encoded by Smp_073400.1, and Phospholipase B-like, encoded by Smp_301430.1. The study identifies these as autophagy-related genes whose expression changed across stages, positioning them alongside the putative TOR orthologue as candidates for further investigation.

The authors frame the work as establishing pharmacological tools rather than delivering treatments. Rapamycin’s activity against both parasite stages in vitro, particularly its lower IC50 in adult worms, is a notable finding, but the experiments were conducted in cultured parasites, and the study positions the tested compounds as tools for investigating schistosome biology rather than as validated therapies.

With praziquantel remaining the mainstay of therapy, the search for new multi-stage active compounds continues. This study adds evidence that autophagy-modulating compounds affect S. mansoni viability and gene expression, identifies a putative TOR orthologue whose expression responds to sublethal rapamycin exposure in adult worms, and provides RT-qPCR measurements of selected autophagy genes across two life-cycle stages. Functional characterization of the highlighted genes will be needed to determine whether these pharmacological observations correspond to biological dependencies that new therapeutics could exploit.

Subject of Research: Effects of autophagy-modulating compounds on viability and autophagy gene expression in Schistosoma mansoni schistosomula and adult worms

Article Title: Classical autophagy-modulating compounds impair viability and alter autophagy gene expression in schistosomula and adult Schistosoma mansoni

Article References: Fischer-Carvalho, A., Lopes-Jesus, L. C., Verjovski-Almeida, S., & Amaral, M. S. (2026). Classical autophagy-modulating compounds impair viability and alter autophagy gene expression in schistosomula and adult Schistosoma mansoni. Frontiers in Parasitology, 5, 1892940. https://doi.org/10.3389/fpara.2026.1892940

Image Credits: AI Generated

DOI: 10.3389/fpara.2026.1892940

Keywords: Schistosoma mansoni, schistosomiasis, autophagy, rapamycin, chloroquine, spautin-1, wortmannin, bafilomycin A1, TOR, gene expression, praziquantel, antischistosomal compounds