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.
Highlights
Neisseria gonorrhoeae is a strict human pathogen that causes the sexually transmitted infection termed gonorrhea
In order to learn if gonococci could influence expression of host genes involved in innate immunity, we first investigated the expression of human Antimicrobial host defense peptide (AMP) LL-37, HBD1 and SLPI in THP-1 macrophage-like monocytic cells infected with live gonococcal strain FA19
The data demonstrated that gonococcal infection led to significant reduction in the expression of LL-37, HBD1 and SLPI compared to uninfected cells using quantitative RT-PCR (Figure 1A)
Summary
Neisseria gonorrhoeae is a strict human pathogen that causes the sexually transmitted infection termed gonorrhea. Gonorrhea is a major worldwide public health problem given its estimated yearly incidence of 87 million infections [1]. In addition to causing a high incidence of infection and disease, the gonococcus is noted for its capacity to develop resistance to antibiotics used in therapy [1]. In 2013, the Center for Disease Control declared antibiotic-resistant N. gonorrhoeae as an urgent threat to public health [2,3,4]. The World Health Organization placed N. gonorrhoeae on the high priority pathogen list for developing new antibiotics [5,6]. We reported that N. gonorrhoeae can survive in Pathogens 2020, 9, 132; doi:10.3390/pathogens9020132 www.mdpi.com/journal/pathogens
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