Identification of a Neisseria gonorrhoeae Histone Deacetylase: Epigenetic Impact on Host Gene Expression

Abstract

Epigenetic reprogramming in macrophages is termed trained innate immunity, which regulates immune tolerance and limits tissue damage during infection. Neisseria gonorrhoeae is a strict human pathogen that causes the sexually transmitted infection termed gonorrhea. Here, we report that this pathogen harbors a gene that encodes a histone deacetylase-like enzyme (Gc-HDAC) that shares high 3D-homology to human HDAC1, HDAC2 and HDAC8. A Gc-HDAC null mutant was constructed to determine the biologic significance of this gene. The results showed that WT gonococci reduced the expression of host defense peptides LL-37, HBD-1 and SLPI in macrophages when compared to its Gc-HDAC-deficient isogenic strain. The enrichment of epigenetic marks in histone tails control gene expression and are known to change during bacterial infections. To investigate whether gonococci exert epigenetic modifications on host chromatin, the enrichment of acetylated lysine 9 in histone 3 (H3K9ac) was investigated using the TLR-focused ChIP array system. The data showed that infection with WT gonococci led to higher H3K9ac enrichment at the promoters of pro-inflammatory mediators’ genes, many TLRs, adaptor proteins and transcription factors, suggesting gene activation when compared to infection with the Gc-HDAC-deficient mutant. Taken together, the data suggest that gonococci can exert epigenetic modifications on host cells to modulate certain macrophage defense genes, leading to a maladaptive state of trained immunity.

Trained immunity and host‐pathogen interactions

“…Finally, some pathogenic bacteria encode their own histone‐modifying enzymes, the human pathogen Neisseria gonorrhoeae , encodes a HDAC‐like enzyme: Gc‐HDAC. This factor was found to reduce the expression of host defense peptides cathelicidin LL‐37, human beta‐defensin 1 (HBD‐1) and secretory leukocyte protease inhibitor (SLPI) in human macrophages via epigenetic modifications of host innate immune genes (Zughaier et al, 2020).…”

Preclinical and clinical progress for HDAC as a putative target for epigenetic remodeling and functionality of immune cells

“…Compared to infection with the histone deacetylase-like enzyme (Gc-HDAC)-deficient mutant, higher H3K9ac enrichment at the promoters of proinflammatory mediator genes, various TLRs, adaptor proteins, and transcription factors were detected after infection with Neisseria gonorrhoeae [69]. The transcription factor ATF-2 correlates with p38, which is associated with stress-induced apoptosis and Toll-like receptor (TLR)-mediated signaling.…”

Epigenetic interaction of microbes with their mammalian hosts

“…( 2012 ) Neisseria gonorrhea Gc-HDAC Histone deacetylase H3 Modification of host chromatin at H3K9ac mark in the promoter region Zughaier et al . ( 2020 ) Mir-146a Suppression of immune response and increase bacterial survival Zughaier et al . ( 2020 ) Porphyromonas gingivalis H3, DNMT1, HDAC1,KDM5B, KDM3C,p300 Induces pro-inflammatory cytokines and Alzheimer's disease-linked gene Imai et al .…”

“…( 2020 ) Mir-146a Suppression of immune response and increase bacterial survival Zughaier et al . ( 2020 ) Porphyromonas gingivalis H3, DNMT1, HDAC1,KDM5B, KDM3C,p300 Induces pro-inflammatory cytokines and Alzheimer's disease-linked gene Imai et al . ( 2009 ); Diomede et al .…”