Abstract
Epigenetic reprogramming plays an important role in shaping immune memory traits within both innate (trained immunity) and adaptive immune cells following Bacillus Calmette-Guérin (BCG) vaccination. However, the precise impact of dynamic DNA methylation alterations on immunological responses after BCG vaccination remains inadequately elucidated. To address this knowledge gap, we conducted a comprehensive study by integrating longitudinal analysis and systems biology approaches. We established a cohort of 284 healthy Dutch individuals, capturing data on genetics, cytokine responses to ex vivo stimulation and genome-wide DNA methylation at baseline, as well as at 14 days and 90 days after BCG vaccination. Our findings revealed distinct patterns of DNA methylation alternations in the short- and long-term following BCG vaccination. Moreover, we established that baseline DNA methylation profiles exert influence on the change in interferon-γ (IFN-γ) production upon heterologous (Staphylococcus aureus) stimulation before and after BCG vaccination. Specifically, we identified the regulation of kisspeptin as a novel pathway implicated in the modulation of IFN-γ production, and this finding has been substantiated through experiment validation. We also observed associations between BCG-induced DNA methylation changes and increased IFN-γ and Interleukin-1 β (IL-1β) production upon S. aureus stimulation. Interestingly, by integrating with genetic, epigenetic, and cytokine response data from the same individuals, mediation analysis demonstrated that most of the identified DNA methylation changes played a mediating role between genetic variants and cytokine responses, for example, the changes of cg21375332 near SLC12A3 gene mediated the regulation of genetic variants on IFN-γ changes after BCG vaccination. Sex-specific effects consistently manifested in DNA methylation changes after BCG vaccination and in the association between baseline methylation and cytokine responses. Together, our findings provide deeper insights into immune response mechanisms, crucial for developing effective epigenetic-based medical interventions for personalized medicine.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
YL was supported by an ERC starting Grant (948207) and a Radboud University Medical Centre Hypatia Grant (2018). CJX was supported by Helmholtz Initiative and Networking Fund (1800167) and Deutsche Forschungsgemeinschaft (DFG) Fund (497673685). MGN was supported by an ERC Advanced Grant (833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
This study was approved by the Arnhem-Nijmegen Medical Ethical Committee (NL58553.091.16).
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Data Availability
All data in the present work have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007498.
