Table 2.

Evidence for Persistent, Detrimental Effects on Nonspecific Immunity.^*

Type of Evidence	Epigenetic Modifications	Reference
In vitro: LPS causes decreased TNF and interleukin-6 production after exposure of monocytes to diverse challenges	LPS-tolerized monocytes decrease H3K4me3 and H3K27ac marks in proinflammatory genes and transcription factors (iRfs, STAT, and HIF-1α)27; LPS induces epigenome loss of H3K27ac marks25	Saeed et al.,25 Novakovic et al.27
Animal models: chronic LCMV infection inhibits TNF, interleukin-2, and interferon-γ production; decreases antigen-induced proliferation, and decreases nonspecific microbicidal activity	CD8+ T cells from chronic LCMV–infected mice have increased DNA methylation and decreased chromatin accessibility in Ifng, Myc, and genes related to T-cell receptor signaling and interleukin-7 and −2 signaling; increased chromatin accessibility in genes related to immune-checkpoint inhibition (PD-1, TIM3, and LAG3)51–53	Seo et al.,51 Ghoneim et al.,52 Miller et al.,53 Ahmed et al.,54 Bengsch et al.,55 Yao et al.56
Animal models: sepsis causes prolonged epigenetic inhibition of interleukin-12 and decreased microbial killing capacity	Six weeks after colon ligation–induced sepsis, interleukin-12 and both p35 and p40 promoters of dendritic cells have decreased H3K4me3 and increased H3K27me2; PRC remains bound and inhibits the interleukin-12 promoter57	Roquilly et al.,41 Wen et al.57
Animal models: infection with E. coli or influenza virus induces detrimental epigenetic marks and inhibits phagocytosis of unrelated organisms	Infection-cured mice have decreased H3K27ac of TLR5 and epigenomic overlap with human monocytes tolerized by LPS41	Roquilly et al.41
Humans: measles increases the risk of TB and other bacterial infections	No studies have yet evaluated whether epigenetic perturbations are part of the postmeasles ablation of adaptive immunity	Turk,36 Perry and Halsey37
Humans: recovery from sepsis is followed by a persistent increased risk of death	No human studies have documented postsepsis induced immune tolerance and immune exhaustion, but no epigenetic studies involving humans post sepsis have yet been completed	van der Poll et al.,42 Prescott et al.43
Humans: hepatitis B or C virus infection increases the risk of bacteremia or bacterial pneumonia	Patients with hepatitis have DNA hypermethylation and closed chromatin conformation that resembles chronic LCMV–induced immune exhaustion	Musher and McKenzie,38 Marrie et al.39
Humans: helminths ablate vaccine immunogenicity	Six months after successful deworming, CD4+ T cells from children who had had schistosomiasis retained DNA hypermethylation of interleukin-12-interferon-y signaling and multiple transcription factors58	Labeaud et al.,47 DiNardo et al.58
Humans: chronic helminth infection increases the risk of TB or HIV infection	Memory CD4+ T cells in patients with HIV have DNA hypermethylation of interleukin-2; 2 years after successful aviremia, CD8+ T cells retain unmethylated DNA marks at PD-159	Kroidl et al.,45 Downs et al.,46 Youngblood et al.59
Humans: after successful therapy, patients with TB are at increased risk for recurrent TB and other infections and retain detrimental DNA hypermethylation marks	After TB therapy, NK cells, monocytes, and CD8+ and CD4+ T cells retain DNA hypermethylation of the interferon-γ, mTOR, TNF–NF-κB, and PI3K–AKT signaling pathways60	Verver et al.,49 Romanowski et al.,50 DiNardo et al.60

^*HIF-1α denotes hypoxia-inducible factor 1α, IRF interferon regulatory factor, LAG3 lymphocyte-activation gene 3, LCMV lymphocytic choriomeningitis virus, NF-κB nuclear factor κB, PD-1 programmed death 1, PI3K phosphatidylinositol 3-kinase, PRC polycomb repressive complex, STAT signal transducer and activator of transcription, TB tuberculosis, TIM3 T-cell immunoglobulin mucin 3, and TLR5 toll-like receptor 5.