Proteome and immunogenicity differences in BCG Pasteur ATCC 35734 and its derivative, the vaccine candidate BCGΔBCG1419c during planktonic growth in 7H9 and Proskauer Beck media.

Bacillus Calmette-Guèrin (BCG) remains as the only vaccine employed to prevent tuberculosis (TB) during childhood. Among factors likely contributing to the variable efficacy of BCG is the modification in its antigenic repertoire that may arise from in vitro growth conditions. Our vaccine candidate, BCGΔBCG1419c, improved protection against TB in mice and guinea pigs with bacteria grown in either 7H9 OADC Tween 80 or in Proskauer Beck Tween 80 media in independent studies. Here, we compared the proteomes of planktonic cultures of BCG and BCGΔBCG1419c, grown in both media. Further to this, we compared systemic immunogenicity ex vivo elicited by both types of BCG strains and cultures when used to vaccinate BALB/c mice. Both the parental strain BCG Pasteur ATCC 35734, and its isogenic mutant BCGΔBCG1419c, had several medium-dependent changes. Moreover, ex vivo immune responses to a multiantigenic (PPD) or a single antigenic (Ag85A) stimulus were also medium-dependent. Then, not only the presence or absence of the BCG1419c gene in our strains under study affected the proteome produced in vitro but also that this was affected by culture medium, potentially leading to changes in the capacity to induce ex vivo immune responses.

Vaccination with BCGΔBCG1419c protects against pulmonary and extrapulmonary TB and is safer than BCG.

A single intradermal vaccination with an antibiotic-less version of BCGΔBCG1419c given to guinea pigs conferred a significant improvement in outcome following a low dose aerosol exposure to M. tuberculosis compared to that provided by a single dose of BCG Pasteur. BCGΔBCG1419c was more attenuated than BCG in murine macrophages, athymic, BALB/c, and C57BL/6 mice. In guinea pigs, BCGΔBCG1419c was at least as attenuated as BCG and induced similar dermal reactivity to that of BCG. Vaccination of guinea pigs with BCGΔBCG1419c resulted in increased anti-PPD IgG compared with those receiving BCG. Guinea pigs vaccinated with BCGΔBCG1419c showed a significant reduction of M. tuberculosis replication in lungs and spleens compared with BCG, as well as a significant reduction of pulmonary and extrapulmonary tuberculosis (TB) pathology measured using pathology scores recorded at necropsy. Evaluation of cytokines produced in lungs of infected guinea pigs showed that BCGΔBCG1419c significantly reduced TNF-α and IL-17 compared with BCG-vaccinated animals, with no changes in IL-10. This work demonstrates a significantly improved protection against pulmonary and extrapulmonary TB provided by BCGΔBCG1419c in susceptible guinea pigs together with an increased safety compared with BCG in several models. These results support the continued development of BCGΔBCG1419c as an effective vaccine for TB.

Changes in Host Response to Mycobacterium tuberculosis Infection Associated With Type 2 Diabetes: Beyond Hyperglycemia.

Tuberculosis (TB) remains as the first cause of death among infectious diseases worldwide. Global incidence of tuberculosis is in part coincident with incidence of type 2 diabetes (T2D). Incidence of T2D is recognized as a high-risk factor that may contribute to tuberculosis dissemination. However, mechanisms which favor infection under T2D are just starting to emerge. Here, we first discuss the evidences that are available to support a metabolic connection between TB and T2D. Then, we analyze the evidences of metabolic changes which occur during T2D gathered thus far for its influence on susceptibility to M. tuberculosis infection and TB progression, such as hyperglycemia, increase of 1AC levels, increase of triglycerides levels, reduction of HDL-cholesterol levels, increased concentration of lipoproteins, and modification of the activity of some hormones related to the control of metabolic homeostasis. Finally, we recognize possible advantages of metabolic management of immunity to develop new strategies for treatment, diagnosis, and prevention of tuberculosis.