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1.
Int J Antimicrob Agents ; 39(3): 232-9, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22240411

ABSTRACT

We have recently shown that in vitro and in vivo exposure of Schistosoma mansoni and Schistosoma haematobium to 5-10mM arachidonic acid (ARA) induces parasite surface membrane disintegration and eventual attrition. Here we report on the optimum ARA dose and post-infection treatment time for maximum schistosome demise in hamsters. A series of four experiments for each schistosome species indicated that oral administration of ARA after patency led to a highly significant (P<0.02 to <0.001) reduction in worm burden accompanied by a significant (P<0.05) decrease in worm egg load. ARA-mediated attrition in vivo appeared to be associated with high titres of serum antibodies to tegumental antigens. In support, serum antibodies from patently infected and ARA-treated hamsters readily bound to the surface membrane of ARA-exposed adult worms, as judged by indirect membrane immunofluorescence. More importantly, addition of serum antibodies and peripheral blood mononuclear cells significantly enhanced ARA-mediated adult worm attrition in vitro. These data together show that the schistosomicidal effect of ARA in laboratory animals is enhanced by immune effectors and is highly efficacious and entirely safe.


Subject(s)
Arachidonic Acid/pharmacology , Schistosoma haematobium/pathogenicity , Schistosoma mansoni/pathogenicity , Schistosomiasis/drug therapy , Schistosomicides/pharmacology , Animals , Antigens, Helminth/metabolism , Arachidonic Acid/administration & dosage , Cell Membrane/drug effects , Cell Membrane/metabolism , Cricetinae , Drug Evaluation, Preclinical , Female , Fluorescent Antibody Technique, Indirect , Leukocytes, Mononuclear/metabolism , Liver/parasitology , Liver/pathology , Male , Mesocricetus , Microscopy, Electron, Scanning , Parasite Egg Count , Schistosoma haematobium/drug effects , Schistosoma mansoni/drug effects , Schistosomiasis/parasitology , Schistosomicides/administration & dosage , Time Factors
2.
Mol Biochem Parasitol ; 178(1-2): 23-8, 2011.
Article in English | MEDLINE | ID: mdl-21524668

ABSTRACT

We predicted, and provided evidence for, the existence of a schistosome tegument-associated Mg(2+)-dependent neutral sphingomyelinase (nSMase), which controls hydrolysis of surface membrane sphingomyelin molecules, thus allowing nutrients, but not host antibodies, to access proteins at the host-parasite interface. While a putative nSMase was identified in a recent Schistosoma mansoni genome sequencing and analysis study, our report is the first to measure nSMase enzymatic activity in Triton X-100-solubilized surface membrane (Sup 1) and whole worm soluble (SWAP) molecules of male and female S. mansoni and Schistosoma haematobium. Neutral, but no acidic, sphingomyelinase activity was readily detectable by the amplex red sphingomyelinase assay, and increased with incubation time and protein amount. Like nSMase family members, the schistosome nSMase activity was significantly (P<0.05 to <0.0001) enhanced by unsaturated fatty acids and phosphatidyl serine and significantly (P<0.01) decreased following exposure to the nSMase specific inhibitor GW4869. Peptides based on the published sequence of S. mansoni putative nSMase and used in a multiple antigen peptide form induced the generation of specific antibodies, which readily bound to the immunogen and to the cognate protein in Sup 1 and SWAP. Immunofluorescence studies suggested the parasite nSMase is located in the worm tegument and gut lining. Studies using RNA interference are in progress to define nSMase role in larval and adult worm surface membrane antigen exposure and unsaturated fatty acid-mediated attrition.


Subject(s)
Schistosoma haematobium/enzymology , Schistosoma mansoni/enzymology , Sphingomyelin Phosphodiesterase/metabolism , Animal Structures/enzymology , Animals , Coenzymes/metabolism , Fatty Acids, Unsaturated/metabolism , Larva/chemistry , Larva/enzymology , Magnesium/metabolism , Microscopy, Fluorescence , Phosphatidylserines/metabolism , Schistosoma haematobium/chemistry , Schistosoma mansoni/chemistry , Sphingomyelins/metabolism
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