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Infection and Immunity, August 2004, p. 4772-4783, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4772-4783.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Anaplasma phagocytophilum Utilizes Multiple Host Evasion Mechanisms To Thwart NADPH Oxidase-Mediated Killing during Neutrophil Infection

Jason A. Carlyon,1 Dalia Abdel Latif,2 Marc Pypaert,3 Paige Lacy,2 and Erol Fikrig1*

Section of Rheumatology, Department of Internal Medicine,1 Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut,3 Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada2

Received 25 January 2004/ Returned for modification 18 March 2004/ Accepted 4 May 2004

Anaplasma phagocytophilum, the etiologic agent of human anaplasmosis, is a bacterial pathogen that specifically colonizes neutrophils. Neutrophils utilize the NADPH oxidase complex to generate superoxide (O2–) and initiate oxidative killing of microorganisms. A. phagocytophilum's unique tropism for neutrophils, however, indicates that it subverts and/or avoids oxidative killing. We therefore examined the effects of A. phagocytophilum infection on neutrophil NADPH oxidase assembly and reactive oxygen species (ROS) production. Following neutrophil binding, Anaplasma invasion requires at least 240 min. During its prolonged association with the neutrophil plasma membrane, A. phagocytophilum stimulates NADPH oxidase assembly, as indicated by increased cytochrome b558 mobilization to the membrane, as well as colocalization of Rac and p22phox. This initial stimulation taxes the host neutrophil's finite oxidase reserves, as demonstrated by time- and bacterial-dose-dependent decreases in secondary activation by N-formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA). This stimulation is modest, however, and does not diminish oxidase stores to nearly the extent that Escherichia coli, serum-opsonized zymosan, FMLP, or PMA do. Despite the apparent activation of NADPH oxidase, no change in ROS-dependent chemiluminescence is observed upon the addition of A. phagocytophilum to neutrophils, indicating that the bacterium may scavenge exogenous O2–. Indeed, A. phagocytophilum rapidly detoxifies O2– in a cell-free system. Once internalized, the bacterium resides within a protective vacuole that excludes p22phox and gp91phox. Thus, A. phagocytophilum employs at least two strategies to protect itself from neutrophil NADPH oxidase-mediated killing.

* Corresponding author. Mailing address: Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, The Anlyan Center for Medical Research and Education, 300 Cedar St., Room 525A, P. O. Box 208031, New Haven, CT 06520-8031. Phone: (203) 737-5635. Fax: (203) 785-7053. E-mail: erol.fikrig{at}yale.edu. {dagger} Present address: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, Lexington, Ky.

Editor: F. C. Fang

Infection and Immunity, August 2004, p. 4772-4783, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4772-4783.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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