Mycobacterium bovis Bacillus Calmette-Guérin Secreting Active Cathepsin S Stimulates Expression of Mature MHC Class II Molecules and Antigen Presentation in Human Macrophages

Abstract

A successful Th cell response to bacterial infections is induced by mature MHC class II molecules presenting specific Ag peptides on the surface of macrophages. In recent studies, we demonstrated that infection with the conventional vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) specifically blocks the surface export of mature class II molecules in human macrophages by a mechanism dependent on inhibition of cathepsin S (Cat S) expression. The present study examined class II expression in macrophages infected with a rBCG strain engineered to express and secrete biologically active human Cat S (rBCG-hcs). Cat S activity was completely restored in cells ingesting rBCG-hcs, which secreted substantial levels of Cat S intracellularly. Thus, infection with rBCG-hcs, but not parental BCG, restored surface expression of mature MHC class II molecules in response to IFN-γ, presumably as result of MHC class II invariant chain degradation dependent on active Cat S secreted by the bacterium. These events correlated with increased class II-directed presentation of mycobacterial Ag85B to a specific CD4+ T cell hybridoma by rBCG-hcs-infected macrophages. Consistent with these findings, rBCG-hcs was found to accelerate the fusion of its phagosome with lysosomes, a process that optimizes Ag processing in infected macrophages. These data demonstrated that intracellular restoration of Cat S activity improves the capacity of BCG-infected macrophages to stimulate CD4+ Th cells. Given that Th cells play a major role in protection against tuberculosis, rBCG-hcs would be a valuable tuberculosis vaccine candidate.

Association between cystatin C and the interaction of pulmonary tuberculosis with chronic diseases

“…An important survival mechanisms of Mycobacterium tuberculosis is preventing contact with active cathepsins by inhibiting phagosome maturation [12]. It is known that some cathepsins (cathepsin B, D and S) interact and contribute to the destruction of invading microorganisms [13]. Consistent with the role of Cys C as a natural inhibitor of cathepsins, cystatin is down-regulated in macrophages infected with Mycobacterium tuberculosis.…”

Interleukin 10 suppresses lysosome-mediated killing of Brucella abortus in cultured macrophages

“…Different members of cathepsins including CtsB, CtsD, CtsG, CtsL and CtsS are known to interact and contribute to killing intracellular Mycobacterium tuberculosis (20,21), Mycobacterium bovis (22), Streptococcus pneumoniae (23) and Listeria monocytogenes (24). Additionally, HexB was also proven to protect macrophage against Mycobacterium marinum (25) in macrophages.…”

Efficient Activation of Human T Cells of Both CD4 and CD8 Subsets by Urease-Deficient Recombinant Mycobacterium bovis BCG That Produced a Heat Shock Protein 70-M. tuberculosis-Derived Major Membrane Protein II Fusion Protein

“…The purpose of vaccination aimed at controlling tuberculosis manifestation is to produce T cells that can immediately respond to antigenic molecules expressed on the surface of M. tuberculosis-infected APCs in the regional lymph nodes. BCG is essentially capable of activating naive CD4 ϩ T cells, but its potency is not convincing and is not suitable for stimulation of naive CD8 ϩ T cells (15,16). Further, macrophages infected with BCG inefficiently activate CD4 ϩ T cells (15).…”

“…BCG activates naive CD4 ϩ T cells substantially but not convincingly and activates naive CD8 ϩ T cells poorly (15,16). The reasons why BCG cannot prevent the development of tuberculosis have not been elucidated fully, but one of the major reasons is its poor immunostimulatory activities, based on the lack of ability to induce phagosomal maturation (17)(18)(19).…”