Epigenetic regulation of defense genes by histone deacetylase1 in human cell line-derived macrophages promotes intracellular survival of Leishmania donovani

Abstract

Leishmania donovani, an intracellular protozoan parasite upon infection, encounters a range of antimicrobial factors within the host cells. Consequently, the parasite has evolved mechanisms to evade this hostile defense system through inhibition of macrophage activation that, in turn, enables parasite replication and survival. There is growing evidence that epigenetic down-regulation of the host genome by intracellular pathogens leads to acute infection. Epigenetic modification is mediated by chromatin remodeling, histone modifications, or DNA methylation. Histone deacetylases (HDACs) removes acetyl groups from lysine residues on histones, thereby leading to chromatin remodeling and gene silencing. Here, using L. donovani infected macrophages differentiated from THP-1 human monocytic cells, we report a link between host chromatin modifications, transcription of defense genes and intracellular infection with L. donovani. Infection with L. donovani led to the silencing of host defense gene expression. Histone deacetylase 1 (HDAC1) transcript levels, protein expression, and enzyme activity showed a significant increase upon infection. HDAC1 occupancy at the promoters of the defense genes significantly increased upon infection, which in turn resulted in decreased histone H3 acetylation in infected cells, resulting in the down-regulation of mRNA expression of host defense genes. Small molecule mediated inhibition and siRNA mediated down-regulation of HDAC1 increased the expression levels of host defense genes. Interestingly, in this study, we demonstrate that the silencing of HDAC1 by both siRNA and pharmacological inhibitors resulted in decreased intracellular parasite survival. The present data not only demonstrate that up-regulation of HDAC1 and epigenetic silencing of host cell defense genes is essential for L. donovani infection but also provides novel therapeutic strategies against leishmaniasis.

Going ballistic: Leishmania nuclear subversion of host cell plasticity

“…With respect to our review, pharmacological interference with miRNAs or HMEs represents another fertile, yet underexplored venue for host-directed, antileishmanial therapy. Inhibition of host cell HDAC activity in L. donovani-infected THP1 cells has been shown to reduce intracellular parasite burden [51,60] and the antidepressant imipramine was linked to increased HDAC 11 expression and reduced survival of antimony-resistant L. donovani in experimental infection [61]. Given that HMEs are key targets for anticancer drug discovery [62], it would be interesting to screen epigenetic compound libraries for antileishmanial activities.…”

“…Recent evidence suggests that Leishmania subverts the histone code to establish the immunometabolomic conditions for its intracellular survival. In L. donovani-and L. amazonensis-infected macrophages, reduced NOS2 expression and production of leishmanicidal NO was linked to induction of histone deacetylase 1 (HDAC1) and the removal of H3K9Ac activation marks, likely via the formation of a repressosome with NF-κB1 homodimers (Figure 3G) [13,51]. We have recently provided direct evidence that L. amazonensis-infected macrophages reduced the expression of various…”

The pathogenicity and virulence of Leishmania - interplay of virulence factors with host defenses

“…Similarly, in L. donovani -infected THP-1 cells, HDAC1 was enriched, which subsequently removes H3K27 acetylation from macrophage defense gene promoters. Thus, Roy et al proposed HDAC1 inhibitors as potential anti-leishmanial agents [ 280 ]. Hijacking host histone H3 modification is a strategy of Leishmania parasites to target inflammasome pathway as well [ 281 ].…”

DNA methylation alterations caused by Leishmania infection may generate a microenvironment prone to tumour development

“…i.e. DNA methylation, histone modifications and non-coding RNA, altering gene expression and thus signalling pathways ( Parmar et al., 2020 ; Roy et al., 2020 ). Marr et al.…”

“…i.e. DNA methylation, histone modifications and non-coding RNA, altering gene expression and thus signalling pathways (Parmar et al, 2020;Roy et al, 2020). Marr et al reported several differentially methylated CpG sites in macrophages upon infection with L. donovani (Marr et al, 2014).…”