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Infection and Immunity, June 2009, p. 2385-2391, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.00023-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Silencing of Host Cell CYBB Gene Expression by the Nuclear Effector AnkA of the Intracellular Pathogen Anaplasma phagocytophilum{triangledown} ,{dagger}

Jose C. Garcia-Garcia,1 Kristen E. Rennoll-Bankert,1 Shaaretha Pelly,1 Aaron M. Milstone,2 and J. Stephen Dumler1*

Dept. of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,1 Dept. of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 212872

Received 7 January 2009/ Returned for modification 14 February 2009/ Accepted 13 March 2009

Coevolution of intracellular bacterial pathogens and their host cells resulted in the appearance of effector molecules that when translocated into the host cell modulate its function, facilitating bacterial survival within the hostile host environment. Some of these effectors interact with host chromatin and other nuclear components. In this report, we show that the AnkA protein of Anaplasma phagocytophilum, which is translocated into the host cell nucleus, interacts with gene regulatory regions of host chromatin and is involved in downregulating expression of CYBB (gp91phox) and other key host defense genes. AnkA effector protein rapidly accumulated in nuclei of infected cells coincident with changes in CYBB transcription. AnkA interacted with transcriptional regulatory regions of the CYBB locus at sites where transcriptional regulators bind. AnkA binding to DNA occurred at regions with high AT contents. Mutation of AT stretches at these sites abrogated AnkA binding. Histone H3 acetylation decreased dramatically at the CYBB locus during A. phagocytophilum infection, particularly around AnkA binding sites. Transcription of CYBB and other defense genes was significantly decreased in AnkA-transfected HL-60 cells. These data suggest a mechanism by which intracellular pathogens directly regulate host cell gene expression mediated by nuclear effectors and changes in host chromatin structure.

* Corresponding author. Mailing address: The Johns Hopkins University School of Medicine, Department of Pathology, 720 Rutland Avenue, Ross 624, Baltimore, MD 21205. Phone: (410) 955-8654. Fax: (443) 287-3665. E-mail: sdumler{at}jhmi.edu

{triangledown} Published ahead of print on 23 March 2009.

{dagger} Supplemental material for this article is available at http://iai.asm.org/.

Editor: A. Camilli

Infection and Immunity, June 2009, p. 2385-2391, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.00023-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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