Journal
BMC INFECTIOUS DISEASES
Volume 14, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1471-2334-14-179
Keywords
Tuberculosis; BCG; T cell activation
Categories
Funding
- Ministry of Health, Labour, and Welfare of Japan [H24-Shinko-Ippan-009, H25-Shinko-Ippan-005]
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Background: Mycobacterium bovis bacillus Calmette-Guerin (BCG) is known to be only partially effective in inhibiting M. tuberculosis (MTB) multiplication in human. A new recombinant (r) urease-deficient BCG (BCG-dHCM) that secretes protein composed of heat shock protein (HSP) 70, MTB-derived CysO and major membrane protein (MMP)-II was produced for the efficient production of interferon gamma (IFN-gamma) which is an essential element for mycobacteriocidal action and inhibition of neutrophil accumulation in lungs. Methods: Human monocyte-derived dendritic cells (DC) and macrophages were differentiated from human monocytes, infected with BCG and autologous T cells-stimulating activity of different constructs of BCG was assessed. C57BL/6 mice were used to test the effectiveness of BCG for the production of T cells responsive to MTB-derived antigens (Ags). Results: BCG-dHCM intracellularly secreted HSP70-CysO-MMP-II fusion protein, and activated DC by up-regulating Major Histcompatibility Complex (MHC), CD86 and CD83 molecules and enhanced various cytokines production from DC and macrophages. BCG-dHCM activated naive T cells of both CD4 and CD8 subsets through DC, and memory type CD4(+) T cells through macrophages in a manner dependent on MHC and CD86 molecules. These T cell activations were inhibited by the pre-treatment of Ag-presenting cells (APCs) with chloroquine. The single and primary BCG-dHCM-inoculation produced long lasting T cells responsive to in vitro secondarily stimulation with HSP70, CysO, MMP-II and H37Rv-derived cytosolic protein, and partially inhibited the replication of aerosol-challenged MTB. Conclusions: The results indicate that introduction of different type of immunogenic molecules into a urease-deficient rBCG is useful for providing polyclonal T cell activating ability to BCG and for production of T cells responsive to secondary stimulation.
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