Leishmania donovani Infection Causes Distinct Epigenetic DNA Methylation Changes in Host Macrophages

Abstract

Infection of macrophages by the intracellular protozoan Leishmania leads to down-regulation of a number of macrophage innate host defense mechanisms, thereby allowing parasite survival and replication. The underlying molecular mechanisms involved remain largely unknown. In this study, we assessed epigenetic changes in macrophage DNA methylation in response to infection with L. donovani as a possible mechanism for Leishmania driven deactivation of host defense. We quantified and detected genome-wide changes of cytosine methylation status in the macrophage genome resulting from L. donovani infection. A high confidence set of 443 CpG sites was identified with changes in methylation that correlated with live L. donovani infection. These epigenetic changes affected genes that play a critical role in host defense such as the JAK/STAT signaling pathway and the MAPK signaling pathway. These results provide strong support for a new paradigm in host-pathogen responses, where upon infection the pathogen induces epigenetic changes in the host cell genome resulting in downregulation of innate immunity thereby enabling pathogen survival and replication. We therefore propose a model whereby Leishmania induced epigenetic changes result in permanent down regulation of host defense mechanisms to protect intracellular replication and survival of parasitic cells.

Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity

“…CpG densities define the chromatin accessibility of the promoters of genes encoding inflammatory cytokines and determine their transcriptional kinetics during pathogen infection 35 , and DNA methylation is stable in peritoneal macrophages during pathogen infection 36 . However, we demonstrated that Dnmt3a-mediated DNA methylation was able to prepare macrophages for rapid and strong activation after viral infection through the regulation of transcription in resident macrophages.…”

Alu repeats as transcriptional regulatory platforms in macrophage responses toM. tuberculosisinfection

“…However, such changes can provide a window to discover novel signaling pathways implicated in host immune responses, and to understand transcriptomic regulatory responses under specific pathophysiological conditions. In this regard, recent studies reported that changes in DNA methylation patterns can rapidly occur in response to certain environmental stimuli (54–56), and Pacis et al. suggested that changes in DNA methylation could contribute to short-term memory in innate immune cells, such as dendritic cells (16).…”

Bacterial infection remodels the DNA methylation landscape of human dendritic cells

“…DNA methylation has been particularly understudied, as a consequence of the belief that methylation marks are highly stable and unlikely to respond to environmental perturbations on a short time scale (Bierne et al 2012;Monticelli and Natoli 2013). Recent work, however, suggests that DNA methylation patterns can rapidly change in response to certain environmental cues (Klug et al 2010;Guo et al 2011;Dowen et al 2012;Marr et al 2014), raising the possibility that rapid changes in DNA methylation might play a role in innate immune responses. To date, no studies have comprehensively investigated the contribution of rapid, active changes in methylation (in contrast to passive changes during cell replication) to the regulatory programs induced by innate immune cells in response to an infectious agent.…”

“…To date, no studies have comprehensively investigated the contribution of rapid, active changes in methylation (in contrast to passive changes during cell replication) to the regulatory programs induced by innate immune cells in response to an infectious agent. More broadly, the few studies in mammalian cells that demonstrate cell division-independent changes in DNA methylation have only focused on a small number of CpG sites and, surprisingly, have suggested that such changes are poorly predictive of changes in gene expression levels (Bruniquel and Schwartz 2003;Klug et al 2010;Guo et al 2011;Marr et al 2014). Here, we report the first comprehensive epigenome and transcriptome analysis of monocyte-derived DCsprofessional antigen-presenting cells that play a central role in bridging innate and adaptive immunity-before and after in vitro infection with live pathogenic bacteria.…”