TY  - JOUR
AU  - Simonis, Alexander
AU  - Theobald, Sebastian J
AU  - Koch, Anna E
AU  - Mummadavarapu, Ram
AU  - Mudler, Julie M
AU  - Pouikli, Andromachi
AU  - Göbel, Ulrike
AU  - Acton, Richard
AU  - Winter, Sandra
AU  - Albus, Alexandra
AU  - Holzmann, Dmitriy
AU  - Albert, Marie-Christine
AU  - Hallek, Michael
AU  - Walczak, Henning
AU  - Ulas, Thomas
AU  - Koch, Manuel
AU  - Tessarz, Peter
AU  - Hänsel-Hertsch, Robert
AU  - Rybniker, Jan
TI  - Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages.
JO  - Molecular systems biology
VL  - 21
IS  - 4
SN  - 1744-4292
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2025-00501
SP  - 341 - 360
PY  - 2025
AB  - Immune memory plays a critical role in the development of durable antimicrobial immune responses. How precisely mRNA vaccines train innate immune cells to shape protective host defense mechanisms remains unknown. Here we show that SARS-CoV-2 mRNA vaccination significantly establishes histone H3 lysine 27 acetylation (H3K27ac) at promoters of human monocyte-derived macrophages, suggesting epigenetic memory. However, we found that two consecutive vaccinations were required for the persistence of H3K27ac, which matched with pro-inflammatory innate immune-associated transcriptional changes and antigen-mediated cytokine secretion. H3K27ac at promoter regions were preserved for six months and a single mRNA booster vaccine potently restored their levels and release of macrophage-derived cytokines. Interestingly, we found that H3K27ac at promoters is enriched for G-quadruplex DNA secondary structure-forming sequences in macrophage-derived nucleosome-depleted regions, linking epigenetic memory to nucleic acid structure. Collectively, these findings reveal that mRNA vaccines induce a highly dynamic and persistent training of innate immune cells enabling a sustained pro-inflammatory immune response.
KW  - Humans
KW  - Macrophages: immunology
KW  - Macrophages: metabolism
KW  - Epigenesis, Genetic
KW  - SARS-CoV-2: immunology
KW  - SARS-CoV-2: genetics
KW  - COVID-19: immunology
KW  - COVID-19: prevention & control
KW  - Histones: metabolism
KW  - Histones: immunology
KW  - Histones: genetics
KW  - Immunologic Memory
KW  - Promoter Regions, Genetic
KW  - Acetylation
KW  - COVID-19 Vaccines: immunology
KW  - Immunity, Innate
KW  - Cytokines: metabolism
KW  - Vaccination
KW  - RNA, Messenger: immunology
KW  - mRNA Vaccines: immunology
KW  - Epigenetic Memory
KW  - Epigenetic Memory (Other)
KW  - G-quadruplex (Other)
KW  - H3K27ac (Other)
KW  - SARS-Cov-2 mRNA Vaccination (Other)
KW  - Trained Innate Immunity (Other)
KW  - Histones (NLM Chemicals)
KW  - COVID-19 Vaccines (NLM Chemicals)
KW  - Cytokines (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - mRNA Vaccines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40133533
C2  - pmc:PMC11965535
DO  - DOI:10.1038/s44320-025-00093-6
UR  - https://pub.dzne.de/record/277881
ER  -