Abstract
BackgroundMiltefosine, an anti-cancer drug that has been successfully repositioned for treatment of Leishmania infections, has recently also shown promising effects against Schistosoma spp targeting all life cycle stages of the parasite. The current study examined the effect of treating Schistosoma mansoni adult worms with miltefosine on exposure of worm surface antigens in vitro.Methodology/Principal findingsIn an indirect immunofluorescence assay, rabbit anti-S.mansoni adult worm homogenate and anti-S. mansoni infection antisera gave strong immunofluorescence of the S. mansoni adult worm surface after treatment with miltefosine, the latter antiserum having previously been shown to synergistically enhance the schistosomicidal activity of praziquantel. Rabbit antibodies that recognised surface antigens exposed on miltefosine-treated worms were recovered by elution off the worm surface in low pH buffer and were used in a western immunoblotting assay to identify antigenic targets in a homogenate extract of adult worms (SmWH). Four proteins reacting with the antibodies in immunoblots were purified and proteomic analysis (MS/MS) combined with specific immunoblotting indicated they were the S. mansoni proteins: fructose-1,6 bisphosphate aldolase (SmFBPA), Sm22.6, alkaline phosphatase and malate dehydrogenase. These antibodies were also found to bind to the surface of 3-hour schistosomula and induce immune agglutination of the parasites, suggesting they may have a role in immune protection.Conclusion/SignificanceThis study reveals a novel mode of action of miltefosine as an anti-schistosome agent. The immune-dependent hypothesis we investigated has previously been lent credence with praziquantel (PZQ), whereby treatment unmasks parasite surface antigens not normally exposed to the host during infection. Antigens involved in this molecular mechanism could have potential as intervention targets and antibodies against these antigens may act to increase the drug’s anti-parasite efficacy and be involved in the development of resistance to re-infection.
Highlights
Despite extensive control efforts, schistosomiasis is still prevalent in many countries [1]
Schistosomiasis (Bilharzia) is a serious public health problem caused by a parasite of genus Schistosoma
We examined the potential that miltefosine could act to expose parasite surface antigens that are normally hidden during natural infection as a way to avoid lethal effects of host immunity
Summary
Schistosomiasis is still prevalent in many countries [1]. Concerns are growing over development of resistance to the only drug available for treatment, namely praziquantel (PZQ), because of its extensive use in control programs for almost three decades [2,3]. The search for an alternative therapeutic control or a combination strategy that is effective against multiple stages of the schistosome life cycle has become necessary [5,6]. The drug later demonstrated effectiveness against antimony-resistant Leishmania [11,12] and (under the trade name Impavido) was approved for oral treatment of visceral leishmaniasis in some countries [13,14,15]. Miltefosine, an anti-cancer drug that has been successfully repositioned for treatment of Leishmania infections, has recently shown promising effects against Schistosoma spp targeting all life cycle stages of the parasite. The current study examined the effect of treating Schistosoma mansoni adult worms with miltefosine on exposure of worm surface antigens in vitro
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