Schistosomiasis, a neglected disease affecting approximately 249 million people globally, is caused by trematodes of the genus Schistosoma. Praziquantel (PZQ) is the mainstay of treatment, but the emergence of resistance represents a growing challenge. This study investigated the role of efflux pumps, particularly P-glycoprotein (Pgp)-like transporters, in PZQ resistance in Schistosoma mansoni.
Methodology: A PZQ-resistant strain of S. mansoni was selected by continuous pressure with the drug, reaching tolerance of up to 1200 mg/kg in model mice (Mus musculus). The activity of efflux pumps was evaluated with ethidium bromide (EtBr) in fluorescence assays in the presence and absence of verapamil, an efflux pump inhibitor. Ex vivo assays analyzed the susceptibility of adult worms to PZQ at varying concentrations of verapamil, while the RNA expression of the SmMDR2 gene, an ortholog of Pgp, was quantified by RT-PCR.
Results: The resistant strain showed higher efflux pump activity and SmMDR2 expression in adult males compared to the susceptible strain. The addition of verapamil partially reversed PZQ resistance, reducing the lethal dose required for both susceptible and resistant males. However, females did not demonstrate significant changes in PZQ resistance associated with the presence of verapamil, indicating distinct mechanisms of susceptibility between the sexes.
Discussion: The findings confirm the role of efflux pumps, especially Pgp-type transporters, in PZQ resistance in male S. mansoni. Inhibition of the pumps by verapamil highlights a potential combination therapy strategy to reverse resistance. These results reinforce the need for continued surveillance and further studies on the genetic mechanisms of resistance to support the development of new approaches to control schistosomiasis.
Reference :
Pinto-Almeida, A., Mendes, T., Armada, A., Belo, S., Carrilho, E., Viveiros, M., & Afonso, A. (2015). The Role of Efflux Pumps in Schistosoma mansoni Praziquantel Resistant Phenotype. PLoS ONE, 10(10), e0140147. https://doi.org/10.1371/journal.pone.0140147
