Elimination of Schistosoma mansoni Adult Worms by Rhesus Macaques Basis for a Therapeutic Vaccine 英文参考文献.docVIP

EliminationofSchistosomamansoniAdultWormsby RhesusMacaques:BasisforaTherapeuticVaccine? R.AlanWilson1*,JanA.M.Langermans2,GovertJ.vanDam3,RichardA.Vervenne2,StephanieL.Hall1, WilliamC.Borges1,GaryP.Dillon1,AlanW.Thomas2,PatriciaS.Coulson1 1Department of Biology, University of York, York, United Kingdom, 2Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands, 3DepartmentofParasitology,LeidenUniversityMedicalCentre,Leiden,TheNetherlands Abstract Background:Amonganimalmodelsofschistosomiasis,therhesusmacaqueisuniqueinthataninfectionestablishesbut egg excretion rapidly diminishes, potentially due to loss of adult worms from the portal system via shunts or death by immuneattack. Principal Findings: To investigate this, six rhesus macaques were exposed to Schistosoma mansoni cercariae and the infection monitored until portal perfusion at 18 weeks. Despite a wide variation in worm numbers recovered, fecal egg output and circulating antigen levels indicated that a substantial population had established in all animals. Half the macaqueshadportalhypertensionbutonlyonehadportacavalshunts,rulingouttranslocationtothelungsasthereason forlossofadultburden.Manywormshadashrunkenandpallidappearance,withdegenerativechangesinintestinesand reproductiveorgans.Tegument,gutepitheliaandmusclesappearedcytologicallyintactbuttheparenchymawasvirtually devoidofcontent.AnearlyandintenseIgGproductioncorrelatedwithlowwormburdenatperfusion,andblood-feeding wormsculturedinthepresenceofserumfromtheseanimalshadstuntedgrowth.Usingimmunoproteomics,gutdigestive enzymes, tegument surface hydrolases andantioxidant enzymes were identified as targets of IgG in the high responder animals. Significance: It appears that worms starve to death after cessation of blood feeding, as a result of antibody-mediated processes. We suggest that proteins in the three categories above, formulated to trigger the appropriate mechanisms operatinginrhesusmacaques,wouldhavebothprophylacticand