Enhanced protective efficacy against tuberculosis provided by a recombinant urease deficient BCG expressing heat shock protein 70-major membrane protein-II having PEST sequence. Issue 50 (7th December 2016)

• Record Type: Journal Article
• Authors: Tsukamoto, Yumiko; Maeda, Yumi; Tamura, Toshiki; Mukai, Tetsu; Mitarai, Satoshi; Yamamoto, Saburo; Makino, Masahiko
• Is Part Of: Vaccine. Volume 34:Issue 50(2016)
• Page Start: 6301
• Page End: 6308
• Publication Date: 2016-12-07
• Subjects: Ag antigen -- APC antigen-presenting cell -- BCG Mycobacterium bovis BCG -- HSP heat shock protein -- MTB Mycobacterium tuberculosis -- MMP major membrane protein -- DC dendritic cell -- r recombinant; Recombinant BCG -- Tuberculosis -- Vaccine; Vaccines -- Periodicals; 615.372
• DOI: 10.1016/j.vaccine.2016.10.069
• Languages: English
• ISSNs: 0264-410X

Abstract

Abstract: Enhancement of the T cell-stimulating ability of Mycobacterium bovis BCG (BCG) is necessary to develop an effective tuberculosis vaccine. For this purpose, we introduced the PEST-HSP70-major membrane protein-II (MMPII)-PEST fusion gene into ureC -gene depleted recombinant (r) BCG to produce BCG-PEST. The PEST sequence is involved in the proteasomal processing of antigens. BCG-PEST secreted the PEST-HSP70-MMPII-PEST fusion protein and more efficiently activated human monocyte-derived dendritic cells (DCs) in terms of phenotypic changes and cytokine productions than an empty-vector-introduced BCG or HSP70-MMPII gene-introduced ureC gene-depleted BCG (BCG-DHTM). Autologous human naïve CD8 + T cells and naïve CD4 + T cells were effectively activated by BCG-PEST and produced IFN-γ in an antigen-specific manner through DCs. These T cell activations were closely associated with phagosomal maturation and intraproteasomal protein degradation in antigen-presenting cells. Furthermore, BCG-PEST produced long-lasting memory-type T cells in C57BL/6 mice more efficiently than control rBCGs. Moreover, a single subcutaneous injection of BCG-PEST more effectively reduced the multiplication of subsequent aerosol-challenged Mycobacterium tuberculosis of the standard H37Rv strain and clinically isolated Beijing strain in the lungs than control rBCGs. The vaccination effect of BCG-PEST lasted for at least 6 months. These results indicate that BCG-PEST may be able to efficiently control the spread of tuberculosis in human.