Epigenetic Silencing of Host Cell Defense Genes Enhances Intracellular Survival of the Rickettsial Pathogen Anaplasma phagocytophilum

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.

Antiapoptotic Activity of Coxiella burnetii Effector Protein AnkG Is Controlled by p32-Dependent Trafficking

“…The Chlamydia trachomatis effector protein NUE is a histone methyltransferase targeting histones (36). AnkA from A. phagocytophilum mediates epigenetic changes at the CYBB promoter (37), leading to a global downregulation of host defense genes (38). How AnkG modulates nuclear function has yet to be determined, but the activity of AnkG is clearly regulated by host cell stress signaling and p32-dependent trafficking.…”

Mechanisms of Obligatory Intracellular Infection with Anaplasma phagocytophilum

“…However, genes encoding the nutritional stress response protein RelA/SpoT and proteins required for the biosynthesis of a quorum-sensing pheromone have not been found in A. phagocytophilum. A. phagocytophilum encodes only two sigma factor homologs: a constitutive factor, 70 , and a single alternative factor, 32 (RpoH). The paucity of alternative sigma factors suggests that A. phagocytophilum relies on the regulation of constitutive 70 -type promoters by transcription factors and posttranscriptional regulation.…”

Fitness and freezing: vector biology and human health

“…Precisely how A. phagocytophilum survives in this inhospitable environment is predicated on its ability to alter functions of the infected granulocyte, including diminished respiratory burst, enhanced inflammatory recruitment of new host cells, and delayed apoptosis of infected cells (10,11). The ability of the pathogen to alter host cell transcriptional programs seems to be key for each of these phenotypic and functional alterations (12)(13)(14). Proven and potential impacts of these alterations are prolonged bacterial survival leading to expanded bacterial populations in the blood of infected mammals, thereby increasing the odds that the next tick bite will result in successful transmission via blood meal acquisition.…”

“…The most likely scenario involves microbial targeting of host metabolic "bottlenecks" or "weak links," that is, pathways where manipulation alters entire functional programs. This could occur by modifying functional programs governed by epigenetic marks that regulate transcription from large physical regions of host chromatin (12) or by subverting host regulators of broad transcriptional programs, such as NF-kB and CCAAT displacement protein (CDP) (22,23). Disease in humans infected with A. phagocytophilum is truly emerging, but the reasons for this are still under investigation.…”