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Infection and Immunity, November 2008, p. 4905-4912, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00851-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Anaplasma phagocytophilum Increases Cathepsin L Activity, Thereby Globally Influencing Neutrophil Function{triangledown}

Venetta Thomas, Swapna Samanta, and Erol Fikrig*

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520

Received 9 July 2008/ Returned for modification 9 August 2008/ Accepted 22 August 2008

Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, is an unusual obligate intracellular pathogen that persists in neutrophils. A. phagocytophilum increases the binding of a repressor, CCAAT displacement protein (CDP), to the gp91phox promoter, thereby diminishing the host oxidative burst. We now show that A. phagocytophilum infection also enhances the binding of CDP to the promoters of human neutrophil peptide 1 and C/EBP{varepsilon}—molecules important for neutrophil defense and maturation—suggesting that this is a general strategy used by this pathogen to alter polymorphonuclear leukocyte function. To explore the mechanism by which A. phagocytophilum increases CDP activity, we assessed the effects of this microbe on cathepsin L, a protease that cleaves CDP into a form with increased DNA binding ability. A. phagocytophilum infection resulted in elevated cathepsin L activity and the proteolysis of CDP. Blocking the action of cathepsin L with a chemical inhibitor or small interfering RNA targeting of this molecule caused a marked reduction in the degree of A. phagocytophilum infection. These data demonstrate that increasing cathepsin L activity is a strategy used by A. phagocytophilum to alter CDP activity and thereby globally influence neutrophil function. As therapeutic options for A. phagocytophilum and related organisms are limited, these results also identify a cellular pathway that may be targeted for the treatment of A. phagocytophilum infection.

* Corresponding author. Mailing address: Section of Infectious Diseases, 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

{triangledown} Published ahead of print on 2 September 2008.

Editor: A. J. Bäumler

Infection and Immunity, November 2008, p. 4905-4912, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00851-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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