A nonspecific component of BCG vaccination

Decades of research on the mechanisms of immunological protection against Mycobacterium tuberculosis, the causative agent of tuberculosis (ТВ), did not allow us to draw a final conclusion about the relative importance of specific pathways when forming protective immunological memory. The BCG vaccine, being the only so far approved tuberculosis vaccine protects children from severe forms of ТВ infection. It is still unclear why BCG does not save from primary infection, reactivation of ТВ and latent carrying. At the same time, the association between BCG vaccination and a reduced risk of non-mycobacterial infections, allergies, cancer and general mortality has been demonstrated. Such nonspecific effects of BCG are dependent mostly on the innate immune cells, rather than on specific memory Т cells. There is evidence of an adjuvant effect of BCG vaccination with respect to the humoral immune response to a variety of childhood vaccines. This review is focused mostly on the analysis of works aimed at studying the relatively recently identified mechanism for generating the non-specific effect of the BCG vaccine, i.e., development of induced natural immunity. This phenomenon is mediated by NOD2 signaling and epigenetic macrophage modification and, due to BCG vaccination, leads to enhanced capacity of macrophages to produce TNFa and IL-6 in response to stimulation by BCG-nonrelated microorganisms or TLR ligands. Induced immunity does not only reshape transmission of immunological signals between the cells of innate immune system, but also induces profound changes in the balance of metabolic pathways, such as glycolysis, oxidative phosphorylation, metabolism of amino acids and fatty acids, being accompanied by enhanced ability of innate immune cells to respond to the secondary stimulation. Realizing these intracellular processes opens up new opportunities for therapeutic intervention into the regulation of immune processes accompanying infectious and inflammatory diseases. In general, an in-depth study of the non-specific component of BCG vaccination should lead to emergence of new ideas about the mechanisms of its protective action, as well as affect development of a new ТВ vaccine. This knowledge can stimulate changes in global vaccination policy, aiming for optimization of vaccination benefits and reduction of childhood morbidity and mortality, as well as decrease of the post-vaccinal complications.

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