Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism

Abstract

The induced expression of nitric oxide synthase (iNOS) controls the intracellular growth of Leishmania in infected macrophages. Histones deacetylases (HDACs) negatively regulate gene expression through the formation of complexes containing transcription factors such as NF-κB p50/50. Herein, we demonstrated the occupancy of p50/p50_HDAC1 to iNOS promoter associated with reduced levels of H3K9Ac. Remarkably, we found increased levels of HDAC1 in L. amazonensis-infected macrophages. HDAC1 upregulation was not found in L. major-infected macrophages. The parasite intracellular load was reduced in HDAC1 knocked-down macrophages, which presented increased nitric oxide levels. HDAC1 silencing led to the occupancy of CBP/p300 to iNOS promoter and the rise of H3K9Ac modification. Importantly, the immunostaining of skin samples from hiporeactive cutaneous leishmaniasis patients infected with L. amazonensis, revealed high levels of HDAC1. In brief, L. amazonensis induces HDAC1 in infected macrophages, which contribute to parasite survival and is associated to hiporeactive stage found in L. amazonensis infected patients.

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

“…Interestingly, decreased methylation of HDAC4 correlated with increased mRNA expression [38]. Earlier reports indicated increased levels of HDAC1 in L. amazonensis infected macrophages [40]. Parasites utilize multiple pathways and mechanisms to mediate epigenetic changes and in turn, control the host defense response to infection.…”

Leishmania amazonensis Subverts the Transcription Factor Landscape in Dendritic Cells to Avoid Inflammasome Activation and Stall Maturation

“…Our data largely extend this list to many other TFs, i.e., spi1, tcf4, myc, zbtb46, irf2, irf8, relb, pparg, spib, or nfil3 (97) that show parasite-driven inhibition of expression in infected DCs, raising important questions on the underlying mechanisms that allow such coordinated modulation of the TRF landscape. In macrophages, Leishmania infection has profound effects on the macrophage epigenetic profile, both at the level of DNA methylation (98) and H3 histone post-translational modifications (30,99,100). We recently provided first evidence that L. am amastigotes induce histone H3K9/14 hypo-acetylation and H3K4 hypotrimethylation at promoters of NF-κB-related, pro-inflammatory genes in infected macrophages in vitro and in infected tissues in vivo (30).…”

Sodium Butyrate Abrogates the Growth and Pathogenesis of Mycobacterium bovis via Regulation of Cathelicidin (LL37) Expression and NF-κB Signaling

“…It has been reported that matrix metalloproteinase (MMP)-1 and -3 expression were regulated by HDAC in M. tuberculosis infection (Moores et al, 2017). In addition, HDAC1 can regulate the expression of iNOS and many cytokines (Calegari-Silva et al, 2018). HDAC3 and HDAC2 has been confirmed as a target of nuclear factor-κB (NF-κB)-mediated inflammation (Leus et al, 2018).…”