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

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 p22^phox. 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 p22^phox and gp91^phox. Thus, A. phagocytophilum employs at least two strategies to protect itself from neutrophil NADPH oxidase-mediated killing.

Editor: F. C. Fang

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