Affiliation:
1. Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520
Abstract
ABSTRACT
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 gp91
phox
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/EBPε—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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Immunology,Microbiology,Parasitology
Reference38 articles.
1. Banerjee, R., J. Anguita, D. Roos, and E. Fikrig. 2000. Cutting edge: infection by the agent of human granulocytic ehrlichiosis prevents the respiratory burst by down-regulating gp91phox. J. Immunol.164:3946-3949.
2. Carlyon, J. A., and E. Fikrig. 2006. Mechanisms of evasion of neutrophil killing by Anaplasma phagocytophilum. Curr. Opin. Hematol.13:28-33.
3. Catt, D., W. Luo, and D. G. Skalnik. 1999. DNA-binding properties of CCAAT displacement protein cut repeats. Cell. Mol. Biol. (Noisy-le-Grand)45:1149-1160.
4. Coqueret, O., G. Berube, and A. Nepveu. 1996. DNA binding by cut homeodomain proteins is down-modulated by protein kinase C. J. Biol. Chem.271:24862-24868.
5. Coqueret, O., N. Martin, G. Berube, M. Rabbat, D. W. Litchfield, and A. Nepveu. 1998. DNA binding by cut homeodomain proteins is down-modulated by casein kinase II. J. Biol. Chem.273:2561-2566.
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