Abstract
ABSTRACTThe protection against tuberculosis induced by the Bacille Calmette Guérin (BCG) vaccine is unpredictable. In our previous study, altered DNA methylation pattern in peripheral blood mononuclear cells (PBMCs) in response to BCG was observed in a subgroup of individuals, whose macrophages killed mycobacteria effectively (‘responders’). These macrophages also showed production of Interleukin-1β (IL-1β) in response to mycobacterial stimuli before vaccination. Here, we hypothesized that the propensity to respond to the BCG vaccine is reflected in the DNA methylome. We mapped the differentially methylated genes (DMGs) in PBMCs isolated from responders/non-responders at the time point before vaccination aiming to identify possible predictors of BCG responsiveness. We identified 43 DMGs and subsequent bioinformatic analyses showed that these were enriched for actin-modulating pathways, predicting differences in phagocytosis. This could be validated by experiments showing that phagocytosis of mycobacteria, which is an event preceding mycobacteria-induced IL-1β production, was strongly correlated with the DMG pattern.
Highlights
DNA methylation is one of the most studied epigenetic modifications in humans, playing a critical role in cellular response, development and differentiation [1,2]
Our previous observation that traits such as an effective release of IL-1β in response to mycobacterial infection existed in subjects who later responded to the Bacille Calmette-Guérin (BCG) vaccine [7] urged us to investigate whether the responders’ immune cells exhibited a distinct DNA methylation pattern prior to BCG vaccination
This study expands on our previous observation of effective IL-1β production in mycobacteriastimulated macrophages obtained from unvaccinated individuals, who later responded to BCG vaccination by reprogramming of DNA methylation and improving anti-mycobacterial efficacy [7]
Summary
DNA methylation is one of the most studied epigenetic modifications in humans, playing a critical role in cellular response, development and differentiation [1,2]. Recent studies show that interaction of host cells with microbial components evokes modulation at the epigenomic level in the host cells Such epigenomic reorganization can be both protective (enhancing host defence and inducing trained immunity, reviewed in [3,4]) and harmful (dysregulating host functions and facilitating the survival of the pathogen, reviewed in [5]). We observed the effective production of IL-1β in response to mycobacterial stimuli of macrophages at the time point before BCG vaccination, suggesting that responders’ immune cells were pre-conditioned to mount a proper response towards mycobacteria. In order to investigate whether this pre-conditioned responsiveness was reflected in differing DNA methylation patterns in responders’ and nonresponders’ immune cells, we reanalysed the DNA methylome data from this time point, including the whole dataset and not just the transcription start site
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