BCG and BCGΔBCG1419c protect type 2 diabetic mice against tuberculosis via different participation of T and B lymphocytes, dendritic cells and pro-inflammatory cytokines

Abstract

Comorbidity between Tuberculosis (TB) and type 2 diabetes (T2D) is one of the greatest contributors to the spread of Mycobacterium tuberculosis (M. tuberculosis) in low-and middle-income countries. T2D compromises key steps of immune responses against M. tuberculosis and it might affect the protection afforded by vaccine candidates against TB. We compared the protection and immune response afforded by the BCGΔBCG1419c vaccine candidate versus that of wild-type BCG in mice with T2D. Vaccination with both BCGΔBCG1419c, BCG or infection with M. tuberculosis reduced weight loss, hyperglycemia, and insulin resistance during T2D progression, suggesting that metabolic changes affecting these parameters were affected by mycobacteria. For control of acute TB, and compared with non-vaccinated controls, BCG showed a dominant T CD4 + response whereas BCGΔBCG1419c showed a dominant T CD8 + /B lymphocyte response. Moreover, BCG maintained an increased response in lung cells via IFN-γ, TNF-α, and IL-4, while BCGΔBCG1419c increased IFN-γ but reduced IL-4 production. As for chronic TB, and compared with non-vaccinated controls, both BCG strains had a predominant presence of T CD4 + lymphocytes. In counterpart, BCGΔBCG1419c led to increased presence of dendritic cells and an increased production of IL-1 β. Overall, while BCG effectively reduced pneumonia in acute infection, it failed to reduce it in chronic infection, whereas we hypothesize that increased production of IL-1 β induced by BCGΔBCG1419c contributed to reduced pneumonia and alveolitis in chronic TB. Our results show that BCG and BCGΔBCG1419c protect T2D mice against TB via different participation of T and B lymphocytes, dendritic cells, and pro-inflammatory cytokines.

Evaluation of early innate and adaptive immune responses to the TB vaccine Mycobacterium bovis BCG and vaccine candidate BCGΔBCG1419c

“…Also, in spleens of BALB/c mice, BCGΔBCG1419c increased T CD3 + CD4 + IFNγ + and T CD3 + CD8 + IFNγ + cells with respect to parental BCG 13 . Moreover, we have observed that BCGΔBCG1419c promote a differential presence in lungs of IFNγ-producing T cells, and activated macrophages in a BALB/c model of active and chronic TB 13 while it changed the relative presence in lungs of B, CD8 + , and dendritic cells, in a BALB/c model of TB-type 2 diabetes 17 . All these findings show that BCG and BCGΔBCG1419c affect the relative composition of adaptive immune cells pre- and post-infection in diverse organs and tissues of vaccinated hosts.…”

“…Recently, the vaccine candidate BCGΔBCG1419c was demonstrated to confer equal and/or better protection against experimental TB compared to its parental strain, BCG Pasteur, in a variety of mouse models (BALB/c 13 , 14 , C57BL/6 15 , 16 , and B6D2F1 [C57BL/6J × DBA/2J] 13 ), including a type 2 diabetic BALB/c model 17 , while in guinea pigs it was more effective than BCG in reducing hematogenous spread at 2 months post-infection 18 . The M. bovis BCG1419c gene encodes a phosphodiesterase activity that hydrolyzes bis-(3′-5′)-cyclic dimeric GMP (c-di-GMP), a molecule which reduces bacterial motility and increases biofilm formation (biofilms are sessile bacteria encased within a matrix of an extracellular polymeric substance) 19 .…”

Evaluation of Early Innate and Adaptive Immune Responses to the TB Vaccine Mycobacterium Bovis BCG and Vaccine Candidate BCGdBCG1419c

“…Also, in spleens of BALB/c mice, BCGDBCG1419c increased T CD3 + CD4 + IFNg + and T CD3 + CD8 + IFNg + cells with respect to parental BCG 13 . Moreover, we have observed that BCGDBCG1419c promote a differential presence in lungs of IFNg-producing T cells, and activated macrophages in a BALB/c model of active and chronic TB 13 while it changed the relative presence in lungs of B, CD8 + , and dendritic cells, in a BALB/c model of TB-type 2 diabetes 17 . All these ndings show that BCG and BCGDBCG1419c affect the relative composition of adaptive immune cells pre-and post-infection in diverse organs and tissues of vaccinated hosts.…”

“…Recently, the vaccine candidate BCGDBCG1419c was demonstrated to confer equal and/or better protection against experimental TB compared to its parental strain, BCG Pasteur, in a variety of mouse models (BALB/c 13,14 , C57BL/6 15,16 , and B6D2F1 [C57BL/6J × DBA/2J] 13 ), including a type 2 diabetic BALB/c model 17 , while in guinea pigs it was more effective than BCG in reducing hematogenous spread at 2 months post-infection 18 . The M. bovis BCG1419c gene encodes a phosphodiesterase activity that hydrolyzes bis-(3′-5′)-cyclic dimeric GMP (c-di-GMP), a molecule which reduces bacterial motility and increases bio lm formation (bio lms are sessile bacteria encased within a matrix of an extracellular polymeric substance) 19 .…”

16α-Bromoepiandrosterone as a new candidate for experimental diabetes–tuberculosis co-morbidity treatment

“…To induce T2D, we used a non-genetic mouse model of diet-induced insulin resistance and pancreatic beta cell insufficiency, as previously reported (24,25). Briefly, male BALB/c 3-week-old mice were fed with a high-fat diet (HFD) containing 45% of calories from fat during the whole course of the experiment.…”