Epigenetic silencing of host cell defense genes enhances intracellular survival of the rickettsial pathogen Anaplasma phagocytophilum.
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.
Garcia-Garcia
Jose C
JC
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Barat
Nicole C
NC
Trembley
Sarah J
SJ
Dumler
J Stephen
JS
D041081:Anaplasma phagocytophilum / Q000502:physiology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D003627:Data Interpretation, Statistical; D016873:Ehrlichiosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D005786:Gene Expression Regulation; D020868:Gene Silencing / Q000276:immunology*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002843:Chromatin; D034741:RNA, Small Interfering; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases