Fig. 2.

Trained immunity and underlying mechanism. Stimulation of naïve monocytes by BCG is accompanied by epigenetic reprogramming and metabolic rewiring in these cells. Histone modifications such as methylation and acetylation leads to chromatin unfolding that facilitates the expression of the genes of proinflammatory factors and metabolic pathways such as glycolysis. Epigenetic changes and metabolic rewiring induced during the initiation of the trained immunity are intricately regulated and work like a positive feedback loop as epigenetic changes enhance the expression of metabolic pathways and metabolites from these pathways cause epigenetic changes in the DNA. These changes vanish only partially after the removal of the stimulus that allows very rapid and enhanced expression of proinflammatory factors following the encounter with unrelated secondary pathogen leading to heterologous protection against this pathogen.