Anaplasma phagocytophilum Modulates gp91[superscript phox] Gene Expression through Altered Interferon Regulatory Factor 1 and PU.1 Levels and Binding of CCAAT Displacement Protein
2005
Thomas, Venetta | Samanta, Swapna | Wu, Caiyun | Berliner, Nancy | Fikrig, Erol
Infection of neutrophil precursors with Anaplasma phagocytophilum, the causative agent of human granulocytic ehrlichiosis, results in downregulation of the gp91[superscript phox] gene, a key component of NADPH oxidase. We now show that repression of gp91[superscript phox] gene transcription is associated with reduced expression of interferon regulatory factor 1 (IRF-1) and PU.1 in nuclear extracts of A. phagocytophilum-infected cells. Loss of PU.1 and IRF-1 correlated with increased binding of the repressor, CCAAT displacement protein (CDP), to the promoter of the gp91[superscript phox] gene. Reduced protein expression of IRF-1 was observed with or without gamma interferon (IFN-[gamma]) stimulation, and the defect in IFN-[gamma] signaling was associated with diminished binding of phosphorylated Stat1 to the Stat1 binding element of the IRF-1 promoter. The diminished levels of activator proteins and enhanced binding of CDP account for the transcriptional inhibition of the gp91[superscript phox] gene during A. phagocytophilum infection, providing evidence of the first molecular mechanism that a pathogen uses to alter the regulation of genes that contribute to an effective respiratory burst.
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