Differential Effects of Prior Exposure to Environmental Mycobacteria on Vaccination withMycobacterium bovisBCG or a Recombinant BCG Strain Expressing RD1 Antigens

2区 · 医学

Article

作者: Rosenkrands, Ida ; Demangel, Caroline ; Cole, Stewart T. ; Garnier, Thierry

ABSTRACTIn silico analysis reveals that most protective antigens expressed by the antituberculous vaccineMycobacterium bovisBCG (BCG) are conserved inM. avium, supporting the hypothesis that exposure to environmental mycobacteria generates cross-reactive immune responses blocking BCG activity. We investigated the impact of sensitization withM. avium,M. scrofulaceum, orM. vaccaeon the protective efficacy of a recombinant BCG strain expressing RD1 antigens (BCG::RD1), using a mouse model of experimental tuberculosis (TB). No evidence that the RD1-encoded antigens ESAT-6, CFP-10, and PPE68 were expressed by these environmental strains could be demonstrated by Western blot analysis. Mice sensitized with each of these strains did not prime cellular immune responses cross-reacting with the immunodominant ESAT-6. Importantly, clearance of BCG::RD1 from the lungs and spleens of mice exposed to each of the environmental strains before vaccination was minimal compared to that of BCG. In mice sensitized withM. avium, increased persistence of BCG::RD1 correlated with stronger antimycobacterial gamma interferon responses and enhanced protection against aerosol infection withM. tuberculosis, compared to BCG. In contrast, animals exposed toM. scrofulaceumorM. vaccaeprior to vaccination with BCG or BCG::RD1 were better protected against TB than were the unsensitized controls. Our results suggest that the inhibitory effect of environmental mycobacteria on the protective efficacy of BCG depends critically on the extent of cross-recognition of antigens shared with the vaccine. In hosts sensitized withM. avium, potent immunogenicity of ESAT-6 and increased persistence of BCG::RD1 may allow this recombinant vaccine to overcome preexisting antimycobacterial responses.

2005-03-15·The Journal of Immunology2区 · 医学

Influence of ESAT-6 Secretion System 1 (RD1) of Mycobacterium tuberculosis on the Interaction between Mycobacteria and the Host Immune System

2区 · 医学

Article

作者: Rojas, Marie-Jésus ; Cole, Stewart T. ; Leclerc, Claude ; Majlessi, Laleh ; Brosch, Roland ; Khun, Huot ; Brodin, Priscille ; Huerre, Michel

AbstractThe chromosomal locus encoding the early secreted antigenic target, 6 kDa (ESAT-6) secretion system 1 of Mycobacterium tuberculosis, also referred to as “region of difference 1 (RD1),” is absent from Mycobacterium bovis bacillus Calmette-Guérin (BCG). In this study, using low-dose aerosol infection in mice, we demonstrate that BCG complemented with RD1 (BCG::RD1) displays markedly increased virulence which albeit does not attain that of M. tuberculosis H37Rv. Nevertheless, phenotypic and functional analyses of immune cells at the site of infection show that the capacity of BCG::RD1 to initiate recruitment/activation of immune cells is comparable to that of fully virulent H37Rv. Indeed, in contrast to the parental BCG, BCG::RD1 mimics H37Rv and induces substantial influx of activated (CD44highCD45RB−CD62L−) or effector (CD45RB−CD27−) T cells and of activated CD11c+CD11bhigh cells to the lungs of aerosol-infected mice. For the first time, using in vivo analysis of transcriptome of inflammatory cytokines and chemokines of lung interstitial CD11c+ cells, we show that in a low-dose aerosol infection model, BCG::RD1 triggered an activation/inflammation program comparable to that induced by H37Rv while parental BCG, due to its overattenuation, did not initiate the activation program in lung interstitial CD11c+ cells. Thus, products encoded by the ESAT-6 secretion system 1 of M. tuberculosis profoundly modify the interaction between mycobacteria and the host innate and adaptive immune system. These modifications can explain the previously described improved protective capacity of BCG::RD1 vaccine candidate against M. tuberculosis challenge.

2004-04-01·Infection and Immunity2区 · 医学

Cell Envelope Protein PPE68 Contributes toMycobacterium tuberculosisRD1 Immunogenicity Independently of a 10-Kilodalton Culture Filtrate Protein and ESAT-6

2区 · 医学

Article

作者: Leclerc, Claude ; Demangel, Caroline ; Cole, Stewart T. ; Cockle, Paul J. ; Brodin, Priscille ; Majlessi, Laleh ; Brosch, Roland

ABSTRACTThe protective efficacy ofMycobacterium bovisBCG can be markedly augmented by stable integration ofMycobacterium tuberculosisgenomic region RD1. BCG complemented with RD1 (BCG::RD1) encodes nine additional proteins. Among them, 10-kDa culture filtrate protein (CFP-10) and ESAT-6 (6-kDa early secreted antigenic target) are low-molecular-weight proteins that induce potent Th1 responses. Using pools of synthetic peptides, we have examined the potential immunogenicity of four other RD1 products (PE35, PPE68, Rv3878, and Rv3879c). PPE68, the protein encoded byrv3873, was the only one to elicit gamma interferon (IFN-γ)-producing cells in C57BL/6 mice infected withM. tuberculosis. Anti-PPE68 T cells were predominantly raised against an epitope mapped in the N-terminal end of the protein. Importantly, inactivation ofrv3873in BCG::RD1 did not modify CFP-10 and ESAT-6 secretion. Moreover, the generation of IFN-γ responses to these antigens following immunization with BCG::RD1 was independent of PPE68 expression. Taken together, these results show that PPE68 is an immunogenic product of the RD1 region, which does not interfere with the secretion and immunogenicity of CFP-10 and ESAT-6.

100 项与 BCG-RD1 相关的药物交易

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