2005 Fiscal Year Final Research Report Summary
Development of DNA vaccine against intracellular protozoa bored on ubiquitin-proteasome system
| Project/Area Number |
16017276
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
HIMENO Kunisuke Kyushu University, Faculty of Medicine, Professor, 大学院医学研究院, 教授 (50112339)
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| Project Period (FY) |
2004 – 2005
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| Keywords | intracellular protozoa / DNA vaccine / gene gun / ubiquitin / ubiquitin-proteasome / CD84T cell / proteasome KO mice / proteasome inhibitor |
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| Research Abstract |
The intracellular protozoan Toxoplasma gondii (T.gondii) is a major opportunistic pathogen in the immunocompromized patient population worldwide. Among the vaccine candidates, the SAG1 protein is the best characterized. This 30-kDa protein is the major surface antigen of T gondii tachyzoites, is highly conserved in T gondii strains, inducing high antibody levels in humans, and is recognized by all the serum samples from infected subjects. CD8^+ T cells play an essential role in the protection against a highly virulent RH strain of T gondii. Some CD8^+ CTL epitopes included in the SAG1 had been defined. However, most vaccine trials including DNA vaccine have resulted in failure agaist the high virulent RH strain except against the cultured and attenuated strain. In the present study, we constructed the vaccine vector encoding ubiquitinated SAG1 which is expected to be processed by "ubiquitin-proteasome pathway" and then be led to MHC class I molecules, resulting in the activation of SAG1-specific CD8^+ T cells.
Mice immunized with the chimeric DNA developed potent protective immunity against Toxoplasma mediated by SAG1-specific CD8^+T cells, while mice immunized with SAG1 gene alone did not. The enhanced immunity was dependent on the ubiquitination of SAG1 that enabled it to be efficiently processed by the proteasome pathway resulting in efficient induction of specific CD8^+T cells. The immunity was dependent on immunoproteasome LMP7 but independent on PA28a/b, a proteasome activator.
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