Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally-derived F2s, and identified a single QTL (LOD=31) on chromosome 6. A sulfotransferase was identified as the causative gene using RNAi knockdown and biochemical complementation assays and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.

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Background: Inthehousedustmite(HDM)Dermatophagoides pteronyssinus,Derp 1,2,5,7,21,and23havebeenidentifiedasthemostimportantallergens.Theaimof thisstudywastodefinehypoallergenicpeptidesderivedfromthesequencesofthe sixallergensandtousethepeptidesandthecompleteallergenstostudyantibody, Tcell,andcytokineresponsesinsensitizedandnonsensitizedsubjects. Methods: IgE reactivity of HDM-allergic and non-HDM-sensitized individuals to 15 HDM allergens was established using ImmunoCAP ISAC technology. Thirtythree peptides covering the sequences of the six HDM allergens were synthesized. Allergens and peptides were tested for IgE and IgG reactivity by ELISA and ImmunoCAP,respectively.Allergenicactivitywasdeterminedbybasophilactivation. CD4+TcellandcytokineresponsesweredeterminedinPBMCculturesbyCFSEdilu-tionandLuminextechnology,respectively. Results: HousedustmiteallergicsshowedIgEreactivityonlytocompleteallergens, whereas 31 of the 33 peptides lacked relevant IgE reactivity and allergenic activity.IgGantibodiesofHDM-allergicandnonsensitizedsubjectsweredirectedagainst peptideepitopesandhigherallergen-specificIgGlevelswerefoundinHDMallergics. PBMCfromHDM-allergicsproducedhigherlevelsofIL-5whereasnon-HDM-sensitized individuals mounted higher levels of IFN-gamma, IL-17, pro-inflammatory cytokines,andIL-10. Conclusion: IgG antibodies in HDM-allergic patients recognize peptide epitopes whicharedifferentfromtheepitopesrecognizedbyIgE.Thismayexplainwhynaturallyoccurringallergen-specificIgGantibodiesdonotprotectagainstIgE-mediated allergicinflammation.AmixofhypoallergenicpeptidescontainingTcellepitopesof themostimportantHDMallergenswasidentified. K E Y W O R D Sallergen,housedustmiteallergy,recombinantallergen,syntheticpeptide,Tcellepitope ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-NonCommercialLicense,whichpermitsuse,distributionandreproduction inanymedium,providedtheoriginalworkisproperlycitedandisnotusedforcommercialpurposes.

Schistosomiasis remains a worldwide endemic cause of chronic and debilitating illness. There are two paradigms that exist in schistosome immunology. The first is that the schistosomule stages are the most susceptible to immune killing, and the second is that the adult stage, through evolution of defense mechanisms, can survive in the hostile host environment. One mechanism that seems to aid the adult worm in evading immune killing is the expression of antioxidant enzymes to neutralize the effects of reactive oxygen and nitrogen species. Here, we challenge one paradigm by targeting adult Schistosoma mansoni worms for immune elimination in an experimental mouse model using two S. mansoni antioxidants, cytosolic superoxide dismutase (SmCT-SOD) and glutathione peroxidase (SmGPX), and a partial coding sequence for a structural protein, filamin, as DNA vaccine candidates. DNA vaccination with SmCT-SOD induced a mean of 39% protection, filamin induced a mean of 50% protection, and SmGPX induced no protection compared to controls following challenge with adult worms by surgical transfer. B-and T-cell responses were analyzed in an attempt to define the protective immune mechanism(s) involved in adult worm killing. SmCT-SOD-immunized mice presented with a T1 response, and filamin-immunized mice showed a mixed T1-T2 response. We provide evidence for natural boosting after vaccination. Our results demonstrate that adult worms can be targeted for immune elimination through vaccination. This represents an advance in schistosome vaccinology and allows for the development of a therapeutic as well as a prophylactic vaccine.

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