DNA Methylation Profiles of Immune Cells From Tuberculosis-Exposed Individuals Overlap With BCG-Induced Epigenetic Changes

Abstract

The mechanism of protection of the only approved tuberculosis (TB) vaccine, Bacillus Calmette Guérin (BCG) is poorly understood. In recent years, epigenetic modifications induced by BCG have been demonstrated to reflect a state of trained immunity. The concept of trained immunity is now explored as a potential prevention strategy for a variety of infections. Studies on human TB immunity are dominated by those using peripheral blood as surrogate markers for immunity. Here, we instead studied the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters, and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to previously reported epigenetic changes and trained immunity in immune cells exposed to the BCG vaccine in human and animal studies. We further demonstrated that similar pathways were epigenetically modified in human macrophages trained with BCG in vitro. Altogether, our study demonstrates that similar epigenetic changes are induced by M. tuberculosis and BCG.