Epigenetic regulation in bacterial infections: targeting histone deacetylases

Abstract

Pathogens have developed sophisticated strategies to evade the immune response, among which manipulation of host cellular epigenetic mechanisms plays a prominent role. In the last decade, modulation of histone acetylation in host cells has emerged as an efficient strategy of bacterial immune evasion. Virulence factors and metabolic products of pathogenic microorganisms alter expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to suppress transcription of host defense genes through epigenetic changes in histone acetylation marks. This new avenue of pathogen-host interactions is particularly important in light of introduction of HDAC inhibitors into clinical practice. Considerable effort is currently being applied to better understand the effects of HDAC inhibitors on the quality of immune responses to pathogens and to characterize the therapeutic potential of these compounds in microbial infections. In this review, we will discuss the recently discovered mechanisms utilized by bacteria to facilitate their survival within infected hosts through subversion of the host acetylation system and the effects of acetylation modulators, including HDAC inhibitors and bromodomain-containing BET protein inhibitors, on innate immune responses against microbial pathogens. Integration of these two lines of experimental evidence provides critical information on the perspectives of epigenetic therapies targeting protein acetylation in infectious diseases.

Keywords: Epigenetics; HDAC inhibitors; histone deacetylase; infection; innate immunity.

Figure 1.

Microbial pathogens developed multiple strategies to evade the immune response through manipulation of the host acetylation system. 2-aminoacetophenone, a quorum sensing molecule released by Pseudomonas aeruginosa induces HDAC1 expression in host cells (Bandyopadhaya et al., 2016). Similarly, Anaplasma phagocytophilum, through its effector molecule ankyrin A upregulates HDAC1 and promotes HDAC1 recruitment to gene promoters (Garcia-Garcia et al., 2009; Rennoll-Bankert et al., 2015). The metalloproteinase NleC produced by enteropathogenic and enterohaemorrhagic Escherichia coli degrades the host HAT p300 (Shames et al., 2011), whereas listeriolysin-O secreted by Listeria monocytogenes promotes histone deacetylation in infected cells through an unknown mechanism (Hamon et al., 2007). RomA, the effector molecule of Legionella pneumophila, blocks acetylation by inducing histone H3 trimethylation (Rolando et al., 2013). All these processes lead to global or promoter-specific histone hypoacetylation, condensation of chromatin structure and suppressed transcription of genes responsible for host defense against microbial infection. 2-AA, 2-aminoacetophenone; Ac; acetylated; 3-Me, tri-methylated; LLO, listeriolysin-O; TF, transcription factor.

Figure 2.

HDAC inhibitors regulate activation of several cell types involved in antimicrobial responses. Activation of inflammatory potential of macrophages is suppressed by inhibitors of class I/II HDACs, but specific inhibition of HDAC6 and HDAC8 facilitates elimination of certain pathogens. SCFAs produced by bacteria and class II HDAC inhibitors stimulate regulatory T cells, which protect the commensal microbiota from elimination by the immune system but could result in blunted immune response to pathogenic microorganisms. Similarly, SCFAs and HDAC inhibitors impair antimicrobial responses of neutrophils. Different classes of HDAC inhibitors and SCFAs stimulate epithelial cell production of CAMPs which contribute to pathogen elimination and stimulate the host immune response. HDAC inhibitors and BET protein inhibitors also prevent infection-related bone resorption by suppressing osteoclast function. CAMPs: cationic antimicrobial peptides; HDACi, HDAC inhibitors; ROS: reactive oxygen species, SCFAs: short chain fatty acids; Tregs: regulatory T cells.