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Review
. 2021 Jan 21;384(3):261-270.
doi: 10.1056/NEJMra2028358.

Postinfectious Epigenetic Immune Modifications - A Double-Edged Sword

Andrew R DiNardo  1 , Mihai G Netea  1 , Daniel M Musher  1
Affiliations
Review

Postinfectious Epigenetic Immune Modifications - A Double-Edged Sword

Andrew R DiNardo et al. N Engl J Med. .
No abstract available

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Figures

Figure 1.
Figure 1.. Epigenetic Mechanisms of Antigen-Nonspecific Immune Memory (Trained Immunity).
DNA is condensed into closed heterochromatin and open euchromatin by wrapping DNA around histone proteins (Panel A). Histone proteins have tails that can be modified, often with marks that make genes more accessible. Some common post-translational modifications include trimethylation of histone 3 at lysine 4 (H3K4me3), which promotes open chromatin. In contrast, trimethylation of histone 3 at lysine 27 (H3K27me3) promotes heterochromatin. The gene-expression implications of certain epigenetic marks are well established (Panel B). DNA methylation decreases transcription-factor binding and decreases gene expression. In contrast, H3K27 acetylation increases chromatin accessibility, which increases the capacity for gene expression. Genes can also be “poised” in a bivalent state simultaneously with both activating (i.e., H3K4me3) and repressive (i.e., H3K27me3) modifications. Epigenetic marks other than acetylation and methylation are not as well studied and are less understood. Long noncoding RNA (lncRNA) acts as a scaffolding to connect topologically associated domains of genes many kilobases apart. The role of histone ubiquination, crotonylation, butyrylation, or lactylation and of RNA acetylation and methylation in long-lasting immune function is still unknown. In macrophages (Panel C), bacille Calmette-Guerin (BCG) and β-glucan induce specific ligand-cell signaling pathways through nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and mammalian target of rapamycin (mTOR), respectively, which results in increased H3K4me3 at the TNF and IL6 promoter. Thereby, when macrophages are exposed to an antigenically different, nonspecific stimulation, there is increased interleukin-6 and tumor necrosis factor (TNF) response. In both monocytes and lymphocytes (Panel D), sepsis, pneumonia, and chronic infections induce detrimental epigenetic scars, such as DNA hypermethylation and closed chromatin conformation that results in decreased effector function when the cells are challenged. CTLA-4 denotes cytotoxic T-lymphocyte–associated protein 4, H3K9me3 trimethylation of histone 3 at lysine 9, H3K27ac acetylation of histone 3 at lysine 27, NFAT nuclear factor of activated T cells, NF-κB nuclear factor κB, PD-1 programmed death 1, and TIM3 T-cell immunoglobulin mucin 3.
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