A Differential DNA Methylome Signature of Pulmonary Immune Cells from Individuals Converting to Latent Tuberculosis Infection

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis, spreads via aerosols and the first encounter with the immune system is with the pulmonary resident immune cells. The role of epigenetic regulations through DNA methylation in the immune cells is emerging. We have previously shown that capacity to kill M. tuberculosis is reflected in the DNA methylome. The aim of this study was to investigate epigenetic modifications in the pulmonary immune cells in a cohort of medical students with a previously documented increased risk of TB exposure, longitudinally. Sputum samples containing alveolar macrophages (AMs) and T cells were collected before and after study subjects worked in hospital departments with a high-risk of TB exposure. DNA methylome analysis revealed that a unique DNA methylation profile was present already at inclusion in subjects who developed latent TB during the study. The profile was both reflected in different overall DNA methylation distribution as well as more profound alterations in the methylation status of a unique set of CpG-sites. Over-representation analysis of the DMGs showed enrichment in pathways related to metabolic reprograming of macrophages and T cell migration and IFN-γ production. In conclusion, we identified a unique DNA methylation signature in individuals, while still IGRA-negative and who later developed latent TB. Epigenetic regulation was found in pathways that have previously been reported to be important in TB. Together the study suggests that DNA methylation status of pulmonary immune cells can predict IGRA conversion.