Abstract
BackgroundSchistosomiasis is a neglected disease caused by a trematode of the genus Schistosoma that is second only to malaria in public health significance in Africa, South America, and Asia. Praziquantel (PZQ) is the drug of choice to treat this disease due to its high cure rates and no significant side effects. However, in the last years increasingly cases of tolerance to PZQ have been reported, which has caused growing concerns regarding the emergency of resistance to this drug.Methodology/Principal FindingsHere we describe the selection of a parasitic strain that has a stable resistance phenotype to PZQ. It has been reported that drug resistance in helminths might involve efflux pumps such as members of ATP-binding cassette transport proteins, including P-glycoprotein and multidrug resistance-associated protein families. Here we evaluate the role of efflux pumps in Schistosoma mansoni resistance to PZQ, by comparing the efflux pumps activity in susceptible and resistant strains. The evaluation of the efflux activity was performed by an ethidium bromide accumulation assay in presence and absence of Verapamil. The role of efflux pumps in resistance to PZQ was further investigated comparing the response of susceptible and resistant parasites in the absence and presence of different doses of Verapamil, in an ex vivo assay, and these results were further reinforced through the comparison of the expression levels of SmMDR2 RNA by RT-PCR.Conclusions/SignificanceThis work strongly suggests the involvement of Pgp-like transporters SMDR2 in Praziquantel drug resistance in S. mansoni. Low doses of Verapamil successfully reverted drug resistance. Our results might give an indication that a combination therapy with PZQ and natural or synthetic Pgp modulators can be an effective strategy for the treatment of confirmed cases of resistance to PZQ in S. mansoni.
Highlights
Schistosomiasis is a neglected tropical disease that affects approximately 249 million people worldwide, 97% of which are located on the African continent
Verapamil is known to block the flow of calcium ions by binding to putative Ca2+ binding site [28,29,30,31], the addition of calcium revealed a reversing effect on the Verapamil inhibitory action on the efflux of ethidium bromide (EtBr), apparently restoring the function of the adult worms efflux pumps, reinforcing the hypothesis raised that the observed accumulation of EtBr in the adult males was due to the effect of this inhibitor on calcium-depended transporters, possibly by indirectly interfering with calcium dependent Pgp ATPases [28,29,30,31]
This strain was obtained by PZQ continuous drug pressure, and this PZQ resistant parasite strain was used to analyse the involvement of efflux pumps in the observed induced PZQ-drug resistance phenotype
Summary
Schistosomiasis is a neglected tropical disease that affects approximately 249 million people worldwide, 97% of which are located on the African continent. It ranks, with malaria and tuberculosis, as a major source of morbidity despite strenuous control efforts [1, 2]. Schistosomiasis treatment relies almost exclusively on the anthelmintic Praziquantel (PZQ). This drug does not prevent reinfection and, with large-scale control programs promoting the extensive use of PZQ for more than 20 years in some African nations, concern regarding the selection of drug resistant parasites has been raised [8,9,10]. In the last years increasingly cases of tolerance to PZQ have been reported, which has caused growing concerns regarding the emergency of resistance to this drug
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