Affiliation:
1. Section of Rheumatology, Department of Internal Medicine
2. Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
3. Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut
Abstract
ABSTRACT
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 (O
2
−
) 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
b
558
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 O
2
−
. Indeed,
A. phagocytophilum
rapidly detoxifies O
2
−
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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Immunology,Microbiology,Parasitology
Cited by
105 articles.
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