Genetic immunization based on the ubiquitin-fusion degradation pathway against Trypanosoma cruzi.
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.
Chou
Bin
B
Department of Microbiology and Immunology, Fukuoka University, Jonan-ku, Fukuoka 814-0180, Japan.
Hiromatsu
Kenji
K
Hisaeda
Hajime
H
Duan
Xuefeng
X
Imai
Takashi
T
Murata
Shigeo
S
Tanaka
Keiji
K
Himeno
Kunisuke
K
D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D014355:Chagas Disease / Q000276:immunology / Q000517:prevention & control*; D003546:Cysteine Endopeptidases / Q000235:genetics; D005260:Female; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics; D009439:Neuraminidase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D016052:Protozoan Vaccines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000276:immunology*; D025801:Ubiquitin / Q000378:metabolism; D014611:Vaccination; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000941:Antigens; D009097:Multienzyme Complexes; D016052:Protozoan Vaccines; D025801:Ubiquitin; D019444:Vaccines, DNA; C071313:LMP-2 protein; C493236:ASP-2 protein, Trypanosoma cruzi; D009439:Neuraminidase; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex