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Infection and Immunity, January 2005, p. 208-218, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.208-218.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Anaplasma phagocytophilum Modulates gp91phox Gene Expression through Altered Interferon Regulatory Factor 1 and PU.1 Levels and Binding of CCAAT Displacement Protein

Venetta Thomas,1 Swapna Samanta,1 Caiyun Wu,1 Nancy Berliner,2 and Erol Fikrig1*

Sections of Rheumatology,1 Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut2

Received 4 June 2004/ Returned for modification 14 July 2004/ Accepted 2 September 2004

Infection of neutrophil precursors with Anaplasma phagocytophilum, the causative agent of human granulocytic ehrlichiosis, results in downregulation of the gp91phox gene, a key component of NADPH oxidase. We now show that repression of gp91phox 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 gp91phox 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 gp91phox 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.

* Corresponding author. Mailing address: Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, S525A, 300 Cedar St., P.O. Box 208031, New Haven, CT 06520-8031. Phone: (203) 785-2453. Fax: (203) 785-7053. E-mail: erol.fikrig{at}yale.edu.

Editor: D. L. Burns

Infection and Immunity, January 2005, p. 208-218, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.208-218.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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