Abstract
Intracellular bacteria have evolved mechanisms that promote survival within hostile host environments, often resulting in functional dysregulation and disease. Using the Anaplasma phagocytophilum–infected granulocyte model, we establish a link between host chromatin modifications, defense gene transcription and intracellular bacterial infection. Infection of THP-1 cells with A. phagocytophilum led to silencing of host defense gene expression. Histone deacetylase 1 (HDAC1) expression, activity and binding to the defense gene promoters significantly increased during infection, which resulted in decreased histone H3 acetylation in infected cells. HDAC1 overexpression enhanced infection, whereas pharmacologic and siRNA HDAC1 inhibition significantly decreased bacterial load. HDAC2 does not seem to be involved, since HDAC2 silencing by siRNA had no effect on A. phagocytophilum intracellular propagation. These data indicate that HDAC up-regulation and epigenetic silencing of host cell defense genes is required for A. phagocytophilum infection. Bacterial epigenetic regulation of host cell gene transcription could be a general mechanism that enhances intracellular pathogen survival while altering cell function and promoting disease.
Highlights
Intracellular pathogens, through a long-standing association with host cells, have evolved mechanisms that allow survival within the often hostile environment of their hosts [1]
Silencing or inhibition of the host protein Histone deacetylase 1 (HDAC1) has a negative effect on intracellular bacterial replication, whereas HDAC1 overexpression leads to defense gene silencing and facilitates intracellular bacterial survival
Previous studies suggest that A. phagocytophilum infection downregulates the expression of key host defense genes such as CYBB, RAC2, MPO and BPI [26]
Summary
Intracellular pathogens, through a long-standing association with host cells, have evolved mechanisms that allow survival within the often hostile environment of their hosts [1]. These mechanisms usually result in dramatic transcriptional changes in infected host cells and in dysregulation of cell functions that potentially lead to disease. Global analysis of mammalian gene expression in response to intracellular bacteria has led to the identification of major pathways affected during infection [2]. While signaling pathways and transcriptional regulators often act on a limited subset of genes, epigenetic regulators tend to more globally control gene expression, and impact major cellular processes such as cell cycle progression and cell differentiation. Dysregulation of epigenetic control mechanisms often leads to dramatic phenotypic changes
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