Lessons from Anaplasma phagocytophilum: chromatin remodeling by bacterial effectors

Abstract

Bacterial pathogens can alter global host gene expression via histone modifications and chromatin remodeling in order to subvert host responses, including those involved with innate immunity, allowing for bacterial survival. Shigella flexneri, Listeria monocytogenes, Chlamydia trachomatis, and Anaplasma phagocytophilum express effector proteins that modify host histones and chromatin structure. A. phagocytophilum modulates granulocyte respiratory burst in part by dampening transcription of several key phagocyte oxidase genes. The A. phagocytophilum protein AnkA localizes to the myeloid cell nucleus where it binds AT-rich regions in the CYBB promoter and decreases its transcription. AT-rich regions of DNA are characteristic of matrix attachment regions (MARs) which are critical for chromatin structure and transcription. MAR-binding proteins, such as SATB1, interact with histone modifying enzymes resulting in altered gene expression. With A. phagocytophilum infection, histone deacetylase 1 (HDAC1) expression is increased and histone H3 acetylation is decreased at the CYBB promoter, suggesting a role for AnkA in altering host epigenetics and modulating gene transcription, at this, and perhaps other loci. This review will focus on how bacterial pathogens alter host epigenetics, by specifically examining A. phagocytophilum AnkA cis-regulation of CYBB transcription and epigenetic changes associated with infection.

Fig. (1)

Control of CYBB expression during myeloid differentiation and neutrophil activation. Transcription factor binding within the –450 to +12 proximal region of the CYBB promoter is important for CYBB repression during myeloid differentiation and neutrophil activation in response to stimuli including IFN-γ and LPS.

Fig. (2)

Predicted model for AnkA control of the CYBB promoter. AnkA is secreted by A. phagocytophilum and translocates to the nucleus of infected cells. AnkA binds AT-rich regions of the CYBB promoter and decreases its expression. It is predicted that AnkA decreases CYBB transcription by recruiting HDAC1 to decrease histone H3 acetylation and induce formation of heterochromatic DNA.

Fig. (3)

OspF dephosphorylates MAPKs in the nucleus. Activation of TLR-4 by LPS results in activation of MAPKs which induce phosphorylation of H3S10 allowing for nucleosome remodeling, NF-κB binding and transcription of inflammatory cytokines and chemokines such as IL-8. OspF is secreted by the Shigella flexneri type III secretion system and translocates to nuclei of infected cells. In the nucleus, OspF irreversibly dephosphorylates MAPKs including ERK1/2 and p38 resulting in decreased H3S10 phosphorylation and transcription of inflammatory cytokines and chemokines.

Fig. (4)

Schematic of LLO and LntA impact on host chromatin. Early in L. monocytogenes infection, LLO inserts into macrophage cell membrane and induces potassium efflux which leads to histone dephosphorylation and deacetylation. A potassium sensor such as HDAC8 could be responsible for altering the histones. During late infection, LntA is predicted to bind BAHD1 and prevent its repression of IFN-stimulated genes.

Fig. (5)

C. trachomatis NUE localizes to the nucleus. NUE has methyltransferase activity which is predicted to alter chromatin structure leading to differential gene transcription upon NUE translocation into the nucleus. The gene targets of NUE have yet to be determined.