Células endoteliais, dapsona e polimorfismos genéticos como moduladores da interação hospedeiro-Schistosoma mansoni sob estresse oxidativo e terapia farmacológica

Abstract

INTRODUCTION: Schistosomiasis is a parasitic disease prevalent in tropical developing countries, and praziquantel (PZQ) is the main drug used for treatment. However, reports of therapeutic failure have been described. Host-related factors, such as the production of antioxidant enzymes—especially catalase—may contribute to maintaining parasite viability. One of dapsone’s metabolites, dapsone hydroxylamine (DDS-NOH), is known to inhibit catalase. Therefore, the reduction of the host’s antioxidant response, particularly through catalase inhibition, could enhance the effect of PZQ. OBJECTIVE: To evaluate, both in vitro and in an experimental model, the effect of dapsone and its metabolite DDS-NOH on the viability of Schistosoma mansoni, and to investigate, in a population residing in an endemic area, the frequency of polymorphisms in the CAT, TSLP, and IL33 genes and their associations with helminth infection and laboratory indicators of morbidity. METHODS: In the in vitro model, adult S. mansoni worms were exposed to DDS-NOH in the presence of H₂O₂, recombinant catalase, or HUVEC endothelial cells. Worm viability was assessed by optical microscopy. In the experimental model, infected mice were treated with PZQ, dapsone, or their combination. Efficacy was evaluated by worm burden, and safety was assessed using clinical and hematological parameters. In a cross-sectional study conducted in a schistosomiasis-endemic area, parasitological tests were performed along with genotyping for CAT rs7943316, TSLP rs1898671, IL33 rs7044343, and IL33 rs928413 polymorphisms, and hematological analyses were conducted. RESULTS: Human endothelial cells exhibited a protective effect on the worms, increasing their viability even under oxidative stress conditions. DDS-NOH was able to reverse this protective effect by inhibiting catalase and reducing worm viability. In the experimental model, the combination of dapsone with PZQ did not enhance antiparasitic efficacy compared to PZQ alone. In humans, the wild-type (CC) genotype of TSLP rs1898671 was associated with a higher frequency of S. mansoni infection, along with changes in laboratory parameters, such as lower levels of hemoglobin and red blood cells in infected individuals with this genotype. CONCLUSION: The host’s pro/antioxidant system may favor the survival of adult S. mansoni worms, and its modulation represents a potential adjuvant therapeutic approach. Genetic factors related to antioxidant responses and innate immunity also influence susceptibility to helminth infection and associated morbidity.