Genetic immunization based on the ubiquitin-fusion degradation pathway against Trypanosoma cruzi |
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Authors: | Bin Chou Kenji Hiromatsu Hajime Hisaeda Takashi Imai Keiji Tanaka |
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Institution: | a Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan b Department of Parasitology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan c Department of Molecular Oncology, The Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan |
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Abstract: | Cytotoxic CD8+ T cells are particularly important to the development of protective immunity against the intracellular protozoan parasite, Trypanosoma cruzi, the etiological agent of Chagas disease. We have developed a new effective strategy of genetic immunization by activating CD8+ T cells through the ubiquitin-fusion degradation (UFD) pathway. We constructed expression plasmids encoding the amastigote surface protein-2 (ASP-2) of T. cruzi. To induce the UFD pathway, a chimeric gene encoding ubiquitin fused to ASP-2 (pUB-ASP-2) was constructed. Mice immunized with pUB-ASP-2 presented lower parasitemia and longer survival period, compared with mice immunized with pASP-2 alone. Depletion of CD8+ T cells abolished protection against T. cruzi in mice immunized with pUB-ASP-2 while depletion of CD4+ T cells did not influence the effective immunity. Mice deficient in LMP2 or LMP7, subunits of immunoproteasomes, were not able to develop protective immunity induced. These results suggest that ubiquitin-fused antigens expressed in antigen-presenting cells were effectively degraded via the UFD pathway, and subsequently activated CD8+ T cells. Consequently, immunization with pUB-ASP-2 was able to induce potent protective immunity against infection of T. cruzi. |
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Keywords: | T cruzi Trypanosoma cruzi UFD ubiquitin-fusion degradation ASP-2 amastigote surface protein-2 UPS ubiquitin proteasome system |
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