Abstract
BackgroundSchistosomiasis—infection with helminth parasites in the genus Schistosoma, including S. mansoni—is a widespread, devastating tropical disease affecting more than 200 million people. No vaccine is available, and praziquantel, the only drug extensively utilized, is currently administered more than 100 million people yearly. Because praziquantel resistance may develop it is essential to identify novel drug targets. Our goal was to investigate the potential of a unique, selenium-containing parasite enzyme thioredoxin glutathione reductase (TGR) as a drug target.Methods and FindingsUsing RNA interference we found that TGR is essential for parasite survival; after silencing of TGR expression, in vitro parasites died within 4 d. We also found that auranofin is an efficient inhibitor of pure TGR (K i = 10 nM), able to kill parasites rapidly in culture at physiological concentrations (5 μM), and able to partially cure infected mice (worm burden reductions of ~60%). Furthermore, two previously used antischistosomal compounds inhibited TGR activity, suggesting that TGR is a key target during therapy with those compounds.ConclusionsCollectively, our results indicate that parasite TGR meets all the major criteria to be a key target for antischistosomal chemotherapy. To our knowledge this is the first validation of a Schistosoma drug target using a convergence of both genetic and biochemical approaches.
Highlights
Schistosomiasis—infection with the helminth parasites in the genus Schistosoma—remains an important infection in many tropical areas, especially Africa
Our results indicate that parasite thioredoxin glutathione reductase (TGR) meets all the major criteria to be a key target for antischistosomal chemotherapy
In this study we have demonstrated that TGR is an essential protein for the survival of S. mansoni and that it meets all the major criteria of an important target for antischistosomal chemotherapy development
Summary
Schistosomiasis ( known as bilharzia)—infection with the helminth parasites in the genus Schistosoma—remains an important infection in many tropical areas, especially Africa. Schistosomiasis—infection with helminth parasites in the genus Schistosoma, including S. mansoni—is a widespread, devastating tropical disease affecting more than 200 million people. Praziquantel, the only drug extensively utilized, is currently administered more than 100 million people yearly. More than 200 million people are infected with schistosomes, a type of parasitic worm. Once in the human host, the parasites turn into larvae and migrate to the liver where they become juvenile worms These mature into 10- to 20-mm-long adult worms and take up long-term residence in the veins draining the gut (Schistosoma mansoni and S. japonicum) or bladder (S. haematobium). Schistosomiasis causes serious health problems (including chronic liver, gut, bladder, and spleen damage) in about 20 million people, making it a disease of great public-health and socioeconomic importance in the developing countries in which it mainly occurs
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