Reversing Post-Infectious Epigenetic-Mediated Immune Suppression

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.

Colorectal Cancer-Associated Immune Exhaustion Involves T and B Lymphocytes and Conventional NK Cells and Correlates With a Shorter Overall Survival

“…The CIBERSORTx tool, which identifies immune cell subpopulations, based on their molecular signature, provides additional information on the immune exhaustion landscape of CRC, and strengthens the concept that, in the TME, exhaustion affects cells other than just T lymphocytes. Expression of FOXP1 and SIRT1, which can suppress antitumor T cells ( 108 ) and promote chemoresistance ( 109 , 110 ), has been found in CRC infiltrating Tregs (FOXP1), CD8 + and memory resting CD4 + cells, but also in naïve and memory B lymphocytes (both FOXP1 and SIRT1). Expression of BATF involves CD8 + cells ( 111 ), but also resting NK cells, while expression of NR4A1 and TOX ( 112 , 113 ) has been found in memory resting CD4 + cells, but also in naïve and memory B cells, respectively.…”

Cholinergic and Neuroimmune Signaling Interact to Impact Adult Hippocampal Neurogenesis and Alcohol Pathology Across Development

“…For example, NFĸB p65 increases gene transcription of a variety of proinflammatory genes, including TLR4, IL-1β, TNFα, CCL2, and COX-2. However, in the presence of HMGB1, NFĸB p50 forms a repressome complex with G9a (Abhimanyu et al, 2021), driving H3K9 methylation at the ChAT and TrkA promotors, reducing cholinergic gene transcription and suppressing the cholinergic neuronal phenotype (Vetreno et al, 2020;Crews et al, 2021). and it is unknown whether these findings extend to females.…”

GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels

“…Nevertheless, functional studies are needed to determine the relevance of this genetic variation on disease pathogenesis [8]. In this sense, epigenomic modifications are particularly ligated to pathological processes behind the chronic phases of infections, even when the first stages have been overcome [21,22]. Several of these modifications have been described in infectious diseases like viral [23], bacterial [24] and specifically, DNAm changes has been reported in parasitic diseases, such as Malaria, Leishmaniasis and Chagas disease [16,25].…”