About: BACKGROUND: Toxoplasmosis causes loss of life, cognitive and motor function, and sight. A vaccine is greatly needed to prevent this disease. The purpose of this study was to use an immmunosense approach to develop a foundation for development of vaccines to protect humans with the HLA-A03 supertype. Three peptides had been identified with high binding scores for HLA-A03 supertypes using bioinformatic algorhythms, high measured binding affinity for HLA-A03 supertype molecules, and ability to elicit IFN-γ production by human HLA-A03 supertype peripheral blood CD8(+ )T cells from seropositive but not seronegative persons. RESULTS: Herein, when these peptides were administered with the universal CD4(+)T cell epitope PADRE (AKFVAAWTLKAAA) and formulated as lipopeptides, or administered with GLA-SE either alone, or with Pam(2)Cys added, we found we successfully created preparations that induced IFN-γ and reduced parasite burden in HLA-A*1101(an HLA-A03 supertype allele) transgenic mice. GLA-SE is a novel emulsified synthetic TLR4 ligand that is known to facilitate development of T Helper 1 cell (TH1) responses. Then, so our peptides would include those expressed in tachyzoites, bradyzoites and sporozoites from both Type I and II parasites, we used our approaches which had identified the initial peptides. We identified additional peptides using bioinformatics, binding affinity assays, and study of responses of HLA-A03 human cells. Lastly, we found that immunization of HLA-A*1101 transgenic mice with all the pooled peptides administered with PADRE, GLA-SE, and Pam(2)Cys is an effective way to elicit IFN-γ producing CD8(+ )splenic T cells and protection. Immunizations included the following peptides together: KSFKDILPK (SAG1(224-232)); AMLTAFFLR (GRA6(164-172)); RSFKDLLKK (GRA7(134-142)); STFWPCLLR (SAG2C(13-21)); SSAYVFSVK((SPA250-258)); and AVVSLLRLLK(SPA(89-98)). This immunization elicited robust protection, measured as reduced parasite burden using a luciferase transfected parasite, luciferin, this novel, HLA transgenic mouse model, and imaging with a Xenogen camera. CONCLUSIONS: Toxoplasma gondii peptides elicit HLA-A03 restricted, IFN-γ producing, CD8(+ )T cells in humans and mice. These peptides administered with adjuvants reduce parasite burden in HLA-A*1101 transgenic mice. This work provides a foundation for immunosense based vaccines. It also defines novel adjuvants for newly identified peptides for vaccines to prevent toxoplasmosis in those with HLA-A03 supertype alleles.   Goto Sponge  NotDistinct  Permalink

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  • BACKGROUND: Toxoplasmosis causes loss of life, cognitive and motor function, and sight. A vaccine is greatly needed to prevent this disease. The purpose of this study was to use an immmunosense approach to develop a foundation for development of vaccines to protect humans with the HLA-A03 supertype. Three peptides had been identified with high binding scores for HLA-A03 supertypes using bioinformatic algorhythms, high measured binding affinity for HLA-A03 supertype molecules, and ability to elicit IFN-γ production by human HLA-A03 supertype peripheral blood CD8(+ )T cells from seropositive but not seronegative persons. RESULTS: Herein, when these peptides were administered with the universal CD4(+)T cell epitope PADRE (AKFVAAWTLKAAA) and formulated as lipopeptides, or administered with GLA-SE either alone, or with Pam(2)Cys added, we found we successfully created preparations that induced IFN-γ and reduced parasite burden in HLA-A*1101(an HLA-A03 supertype allele) transgenic mice. GLA-SE is a novel emulsified synthetic TLR4 ligand that is known to facilitate development of T Helper 1 cell (TH1) responses. Then, so our peptides would include those expressed in tachyzoites, bradyzoites and sporozoites from both Type I and II parasites, we used our approaches which had identified the initial peptides. We identified additional peptides using bioinformatics, binding affinity assays, and study of responses of HLA-A03 human cells. Lastly, we found that immunization of HLA-A*1101 transgenic mice with all the pooled peptides administered with PADRE, GLA-SE, and Pam(2)Cys is an effective way to elicit IFN-γ producing CD8(+ )splenic T cells and protection. Immunizations included the following peptides together: KSFKDILPK (SAG1(224-232)); AMLTAFFLR (GRA6(164-172)); RSFKDLLKK (GRA7(134-142)); STFWPCLLR (SAG2C(13-21)); SSAYVFSVK((SPA250-258)); and AVVSLLRLLK(SPA(89-98)). This immunization elicited robust protection, measured as reduced parasite burden using a luciferase transfected parasite, luciferin, this novel, HLA transgenic mouse model, and imaging with a Xenogen camera. CONCLUSIONS: Toxoplasma gondii peptides elicit HLA-A03 restricted, IFN-γ producing, CD8(+ )T cells in humans and mice. These peptides administered with adjuvants reduce parasite burden in HLA-A*1101 transgenic mice. This work provides a foundation for immunosense based vaccines. It also defines novel adjuvants for newly identified peptides for vaccines to prevent toxoplasmosis in those with HLA-A03 supertype alleles.
subject
  • Virology
  • Immune system
  • Immunostimulants
  • Transfusion medicine
  • Blood antigen systems
  • Exercise physiology
  • Gene complexes
  • Genes on human chromosome 6
  • Human MHC haplogroups
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