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.
In schistosomiasis mansoni, hepatic granulomatous inflammation surrounding parasite eggs is mediated by CD4؉ T helper (Th) cells sensitized to schistosomal egg antigens (SEA). We previously showed that a prominent lymphoproliferative response of CD4 ؉ Th cells from schistosome-infected C57BL/6 (BL/6) mice was directed against a 62-kDa component of SEA. A partial amino acid sequence of the 62-kDa component was found to be identical with one present in the enzyme phosphoenolpyruvate carboxykinase (PEPCK). Based on this sequence, a cDNA clone containing the entire coding region of PEPCK was identified, and the full recombinant Schistosoma mansoni PEPCK (rSm-PEPCK) of 626 amino acids was purified from a prokaryotic expression system. rSm-PEPCK strongly stimulated a specific T-cell hybridoma, 4E6, as well as CD4؉ Th cells from SEA-immunized BL/6 mice and from infected BL/6, CBA, and BALB/c mice. In the infected mice, rSm-PEPCK elicited significant gamma interferon production as well as, to a lesser extent, production of interleukin-2 and -5. In BL/6 and BALB/c mice, the CD4 ؉ Th cell response to rSm-PEPCK was greater than that directed against the egg antigen Sm-p40; conversely, CBA mice responded better to Sm-p40 than to Sm-PEPCK. A 12-amino-acid region (residues 398 to 409: DKSKDPKAHPNS) was demonstrated to contain a T-cell epitope; synthetic peptides containing this epitope significantly stimulated specific hybridoma 4E6 and polyclonal CD4؉ Th cells. The identification and characterization of immunogenic egg components will contribute to the understanding and possible control of T-cell-mediated schistosomal disease.The main immunopathological damage in Schistosoma mansoni infection consists of granulomatous inflammation around parasite eggs in the liver and intestines, which may lead to scarring, portal hypertension, hemorrhage, and death (4, 39). There is considerable variation in the overall severity of this disease, both in humans and in mice. Mice of the C3H and CBA strains develop significantly larger egg granulomas than do those of the C57BL/6 (BL/6) strain (9, 15).Granulomatous inflammation is a complex hypersensitivity reaction that involves the recruitment of various cells, the activation of numerous mediators, including cytokines, and the synthesis of matrix proteins. Granuloma formation is known to be strictly dependent on CD4 ϩ T helper (Th) cells specific for schistosomal egg antigens (SEA) (18, 27), and there is strong evidence that it can be mediated by Th-1-and Th-2-type CD4 ϩ Th cells (11,17,33,40,48). The CD4 ϩ Th cells become activated following specific recognition of accessory cell-bound major histocompatibility complex (MHC) class II molecules harboring selected SEA-derived peptides. We previously investigated the nature of the anti-SEA T-cell repertoire by using CD4 ϩ Th cells from infected mice as well as panels of specific T-cell hybridomas. C3H and CBA mice display strong polyclonal T-cell responses to Sm-p40, a demonstrated major egg immunogen in H-2 k mice (7,19,20). By comparison, in B...
Schistosoma mansoni, an intravascular parasite, has evolved a number of immune evasion mechanisms to establish itself in the host, such as antioxidant enzymes. Our laboratory has demonstrated that the highest levels of certain antioxidant enzymes are found in adult worms, which are the least susceptible to immune killing. Vaccination of mice with naked DNA constructs containing the gene encoding Cu/Zn cytosolic superoxide dismutase (SmCT-SOD) showed significant levels of protection compared to a control group, and our data demonstrate that the adult worms are a target of the immune response that confers resistance in SmCT-SOD DNA-vaccinated mice. Because SmCT-SOD shows significant identity with the human homologue, we evaluated the reactivity of anti-SmCT-SOD antibodies derived from SmCT-SOD-immunized mice and rabbits and from S. mansoni-infected individuals to human superoxide dismutase (hSOD) and SmCT-SOD parasite-specific peptides to assess the potential for autoimmune responses from immunization with the recombinant molecule. In addition, we evaluated the ability of various SmCT-SOD adjuvant-delivered immunizations to induce cross-reactive antibodies. Both mouse and rabbit antibodies generated against SmCT-SOD recognized the denatured form of hSOD. The same antibodies did not recognize nondenatured hSOD. Sera from infected individuals with different clinical forms of schistosomiasis recognized SmCT-SOD but not hSOD. Antibodies from mice immunized with different SmCT-SOD-containing formulations of both DNA and protein were able to recognize SmCT-SOD-derived peptides but not soluble hSOD. All together, these findings serve as a basis for developing a subunit vaccine against schistosomiasis.Schistosomiasis remains an endemic problem in over 76 countries, although approaches to reduce transmission and morbidity as well as to improve sanitation, mollusciciding and mass chemotherapy, have been attempted (3, 13). Vaccine development to control schistosomiasis is a high priority, as it would offer the potential of cost-efficient, long-lasting prophylaxis (2, 65). Schistosoma mansoni, an intravascular parasite, lives in a hostile environment in close contact with host humoral and cellular cytotoxic factors. Larval parasite killing mechanisms include the release of oxidants by eosinophils, neutrophils, and macrophages potentiated by antibodies and/or cytokines (8,12,16,31,32). However, to establish itself in the host, the parasite has evolved a number of immune evasion mechanisms (17,39,51,60), such as antioxidant enzymes (7,11,30,37). These are essential enzymes involved in the prevention of reactive oxygen species-derived damage. Evidence for the involvement of schistosome antioxidant enzymes, such as cytosolic superoxide dismutase (SmCT-SOD) and glutathione peroxidase (SmGPX), in immune evasion has been presented elsewhere (39). SmCT-SOD and GPX localize to the host-parasite interface (worm tegument and gut epithelium of the adult but not the larval schistosome) (41) and show developmental regulation (29,41,42) wit...
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