Enhanced protective efficacy against tuberculosis provided by a recombinant urease deficient BCG expressing heat shock protein 70-major membrane protein-II having PEST sequence |
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| Affiliation: | 1. Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, 4-2-1 Aobacho, Higashimurayama, Tokyo, Japan;2. Department of Mycobacterium Reference and Research, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, 3-1-24 Matsuyama, Kiyose, Tokyo, Japan;3. Japan BCG Laboratory, 3-1-5 Matsuyama, Kiyose, Tokyo, Japan;1. Mycobacteria Research Laboratories, Colorado State University, USA;2. The Infectious Disease Research Institute, Seattle, USA;1. Communicable Diseases Policy Research Group, Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, UK;2. Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597;1. London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK;1. College of Life Science, Zaozhuang University, Zaozhuang 277160, China;2. College of Medical Science, Zaozhuang Vocational College, Zaozhuang 277800, China;3. Research Institute of Chemical Defense, Beijing 102205, China;1. Department of Microbiology, Immunology & Parasitology, LSUHSC-New Orleans, LA 70112, USA;2. Internal Medicine, LSUHSC-New Orleans, LA 70112, USA;3. The Louisiana Vaccine Center, LSUHSC-New Orleans, LA 70112, USA |
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| 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. |
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| Keywords: | Recombinant BCG Tuberculosis Vaccine |
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