Abstract
The immune response must balance the pro-inflammatory, cell-mediated cytotoxicity with the anti-inflammatory and wound repair response. Epigenetic mechanisms mediate this balance and limit host immunity from inducing exuberant collateral damage to host tissue after severe and chronic infections. However, following treatment for these infections, including sepsis, pneumonia, hepatitis B, hepatitis C, HIV, tuberculosis (TB) or schistosomiasis, detrimental epigenetic scars persist, and result in long-lasting immune suppression. This is hypothesized to be one of the contributing mechanisms explaining why survivors of infection have increased all-cause mortality and increased rates of unrelated secondary infections. The mechanisms that induce epigenetic-mediated immune suppression have been demonstrated in-vitro and in animal models. Modulation of the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR), nuclear factor of activated T cells (NFAT) or nuclear receptor (NR4A) pathways is able to block or reverse the development of detrimental epigenetic scars. Similarly, drugs that directly modify epigenetic enzymes, such as those that inhibit histone deacetylases (HDAC) inhibitors, DNA hypomethylating agents or modifiers of the Nucleosome Remodeling and DNA methylation (NuRD) complex or Polycomb Repressive Complex (PRC) have demonstrated capacity to restore host immunity in the setting of cancer-, LCMV- or murine sepsis-induced epigenetic-mediated immune suppression. A third clinically feasible strategy for reversing detrimental epigenetic scars includes bioengineering approaches to either directly reverse the detrimental epigenetic marks or to modify the epigenetic enzymes or transcription factors that induce detrimental epigenetic scars. Each of these approaches, alone or in combination, have ablated or reversed detrimental epigenetic marks in in-vitro or in animal models; translational studies are now required to evaluate clinical applicability.
Highlights
Epigenetic mechanisms guide gene expression to maintain homeostasis by balancing the nature of expressed and nonexpressed genes
PD-1 signaling through Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) activates AMPK, which is an inhibitor of mammalian target of rapamycin (mTOR) signaling, leading to downregulation of HIF-1a and MYC, which in turn governs the transcription of the glycolytic enzymes such as GLUT1, thereby decreasing cellular metabolism
PU.1 facilitates myeloid gene transcription, while tolerance is associated with binding of co-repressor BCL6 to PU.1, disruption of the NFkB active heterodimer and epigenetic silencing via high-mobility group box-1 protein (HMGB1), RelB, NCoR-HDAC3-p50 repressome (Figure 2), increased SMYD5 and G9a methyltransferase and decreased chromatin accessibility due to reduced recruitment of BRG1-NRC
Summary
Epigenetic mechanisms guide gene expression to maintain homeostasis by balancing the nature of expressed and nonexpressed genes This balance can be perturbed either by pathogen- induced epigenetic changes, such as through Rv1998 antigen secreted by Mycobacterium tuberculosis (Mtb) [1] or by chronic and severe stimulation of the immune system as in case of LCMV [2], HCV [3], sepsis [4], Schistosomiasis [5] and TB [6]. We review the growing literature of in-vitro and animal model studies demonstrating how to block or reverse infection induced epigenetic-mediated immune suppression and postulate how these approaches could become clinically relevant to decrease post-infectious morbidity and mortality
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