Reduction of Mycobacterium tuberculosis infection in Bacillus Calmette Guerin immunized people is due to training of innate immunity

Preventing Mycobacterium tuberculosis infection by enhancement of innate immunity

“…We recently demonstrated that across different geographical settings BCG can prevent Mycobacterium tuberculosis infection with a vaccine efficacy of up to 27% [2]. The reduced probability of infection in BCG immunised exposed children was compatible with an enhancement of innate immunity of macrophages by BCG eliminating infection [3]. The enhancement of antimycobacterial activity of macrophages by Vitamin A and D described could equally be used to prevent the establishment of the infection event at the entry point of M. tuberculosis in the lung.…”

Stimulation of Nucleotide Oligomerization Domain and Toll-Like Receptors 2 to Enhance the Effect of Bacillus Calmette Guerin Immunization for Prevention of Mycobacterium Tuberculosis Infection: Protocol for a Series of Preclinical Randomized Controlled Trials

“…Bacillus calmette guerin (BCG) immunization has been associated with a reduced reactivity of interferon (IFN) gamma release assays for Mycobacterium tuberculosis (MTB) infection in exposed children [1]. This finding is compatible with a reduction of infection because of an abortion of infection before engagement of T-effector cells induced by an enhancement of innate immunity by BCG immunization [2,3]. Previous vaccination studies used mouse models with infection of all mice and vaccine efficacy identified by reduced organ colony forming units.…”

“…Should a reduction of MTB infection in BCG immunized mice be confirmed with the above experiment, further experiments can be conducted investigating both the underlying mechanisms as well as ways to enhance the effect of BCG by identification of compounds able to reduce MTB infection by enhancing innate immunity with and without concomitant BCG immunization. Components of innate immunity potentially modifiable are pattern recognition receptor signaling including toll-like receptor 2 (TLR2) signaling by action of muramyl dipeptide (MDP) derivatives with a single octanoyl or stearoyl fatty acid chain, nucleotide oligomerization domain (NOD) 1 by H-Ala-D-γ-Glu-diaminopimelic acid, and NOD 2 signaling also by use of MDP, which is a stimulator of NOD expression and possibly murabutide (see rationale and protocol in [3]), a nontoxic derivative of MDP [5-10]. Simultaneous stimulation of TLR 2 and NOD 2 has hereby been shown to be associated with a synergistic effect on antimycobacterial cytokine production [6].…”

“…The most powerful stimulator of innate immunity may be yeast-derived beta glucan through stimulation of the intramembranous C-type lectin receptor dectin-1 [11,12]. Essential effector mechanism of innate immunity coupled to pattern recognition receptor stimulation is the induction of tumor necrosis factor (TNF) and IFN gamma production in monocytes through action of nuclear factor kappa B. TNF and IFN gamma enhance autophagy and production of nitric oxide metabolites toxic to mycobacteria [3,13].…”