A novel recombinant BCG-expressing pro-apoptotic protein BAX enhances Th1 protective immune responses in mice

Abstract

One-third of the world's population is infected with Mycobacterium tuberculosis (MTB). The protective efficacy of bacille Calmette Guérin (BCG) vaccine against tuberculosis (TB) in adults is highly controversial even though the BCG vaccine has been available for more than 90 years. Because BCG is effective against infantile tuberculosis meningitis and miliary tuberculosis in young children and provides cost-effective prevention from tuberculosis for developing countries, it would be desirable to modify the existing BCG vaccine to provide more comprehensive protection. In our study, we constructed a novel recombinant BCG strain expressing pro-apoptotic BAX (rBCG::BAX) and demonstrated that it significantly induced the apoptosis of macrophages infected with rBCG::BAX both in vitro and in vivo. In addition, it significantly enhanced Ag85B-specific IFN-γ enzyme-linked immunospot responses, IFN-γ secretion, IL-2 secretion and the ratio of Ag85B-specific IgG2b/IgG1, and it significantly decreased Ag85B-specific IL-4. Furthermore, it presumably facilitated antigen presentation by inducing a significant up-regulation in the expression of MHC-II and B7.1 (CD80) co-stimulatory molecules on macrophages. In conclusion, these results suggest that the rBCG::BAX strain elicited predominantly a Th1 protective immune responses and might be a potential tuberculosis vaccine candidate for further study.

Transcriptional Profiling of Mycobacterium tuberculosis Exposed toIn VitroLysosomal Stress

“…Our analysis singled out PPE41 based on its consistent induced profile observed in M. tuberculosis from infected BMMO (11) and human macrophages (13), mouse lungs (42), and iLivE M. tuberculosis (see Table S1). The PE25/PPE41 protein complex was shown to induce dendritic cell activation and drive Th2-biased immune responses (59), whereas Th1-biased immune responses have long been known to be protective against tuberculosis (60). Downregulation of ESAT-6-like proteins and upregulation of PPE41 in iLivE M. tuberculosis indicates that the lysosomal environment contributes to subversion of the host immune system by M. tuberculosis toward nonprotective immune responses.…”

Role of Interferons in the Development of Diagnostics, Vaccines, and Therapy for Tuberculosis

“…Hence, several approaches to TB vaccine development employing the use of proapoptotic vaccine candidates in the form of DNA vaccine, recombinant Mtb, or recombinant BCG platforms have been tested, demonstrating the induction of IFN- γ production and protection against Mtb in mice [101–104]. …”

FOXO3 Transcription Factor Regulates IL-10 Expression in Mycobacteria-Infected Macrophages, Tuning Their Polarization and the Subsequent Adaptive Immune Response

“…The global TB burden has increased due to emergence of drug-resistant Mycobacterium tuberculosis (M.tb) strains and the limited protection conferred by M. bovis BCG against pulmonary TB (2). Targeting the host effectors, involved in TB immune response, has been proposed as a viable adjunct therapy for elimination of both drug-sensitive and drug-resistant TB (3) or to enhance the BCG protective efficacy (4). Therefore, there is a critical need to uncover the TB host responsive clues that might lead to the development of novel host-directed approaches for better treatment or prevention of TB.…”