Targeting Macrophage Histone H3 Modification as a Leishmania Strategy to Dampen the NF-κB/NLRP3-Mediated Inflammatory Response

Abstract

Summary: Aberrant macrophage activation during intracellular infection generates immunopathologies that can cause severe human morbidity. A better understanding of immune subversion strategies and macrophage phenotypic and functional responses is necessary to design host-directed intervention strategies. Here, we uncover a fine-tuned transcriptional response that is induced in primary and lesional macrophages infected by the parasite Leishmania amazonensis and dampens NF-κB and NLRP3 inflammasome activation. Subversion is amastigote-specific and characterized by a decreased expression of activating and increased expression of de-activating components of these pro-inflammatory pathways, thus revealing a regulatory dichotomy that abrogates the anti-microbial response. Changes in transcript abundance correlate with histone H3K9/14 hypoacetylation and H3K4 hypo-trimethylation in infected primary and lesional macrophages at promoters of NF-κB-related, pro-inflammatory genes. Our results reveal a Leishmania immune subversion strategy targeting host cell epigenetic regulation to establish conditions beneficial for parasite survival and open avenues for host-directed, anti-microbial drug discovery. : Lecoeur et al. demonstrate that the parasite Leishmania amazonensis modifies expression of NF-kB-related genes and prevents NLRP3 inflammasome activation of host macrophages in vitro and in vivo by changing histone H3 modifications at the promotor of pro-inflammatory genes. This mechanism of immune subversion opens avenues for host-directed, anti-leishmanial therapies. Keywords: Leishmania amazonensis, amastigotes, lesional macrophage, NF-κB, NLRP3 inflammasome, H3 acetylation, H3 methylation, epigenetics, histone