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Department of Pathology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756 1 This work was supported by awards from the Hitchcock Foundation and an Institutional Autoimmune and Connective Tissue Training Grant 5T32 AR07576 (to T.K.) and National Institutes of Health Grant NS-27321 (to W.F.H.).
We have developed a mouse brain abscess model by using
Staphylococcus aureus, one of the main etiologic agents
of brain abscesses in humans. Direct damage to the blood-brain barrier
was observed from 24 h to 7 days after S. aureus
exposure as demonstrated by the accumulation of serum IgG in the brain
parenchyma. Evaluation of brain abscesses by immunohistochemistry and
flow cytometry revealed a prominent neutrophil infiltrate. To address
the importance of neutrophils in the early containment of S.
aureus infection in the brain, mice were transiently depleted
of neutrophils before implantation of bacteria-laden beads.
Neutrophil-depleted animals consistently demonstrated more severe brain
abscesses and higher CNS bacterial burdens compared with control
animals. S. aureus led to the induction of numerous
chemokines in the brain, including macrophage-inflammatory protein
(MIP)-1
/CCL3, MIP-1
/CCL4, MIP-2/CXCL1, monocyte chemoattractant
protein-1/CCL2, and TCA-3/CCL1, within 6 h after bacterial
exposure. These chemokines also were expressed by both primary cultures
of neonatal mouse microglia and astrocytes exposed to heat-inactivated
S. aureus in vitro. Because neutrophils constitute the
majority of the cellular infiltrate in early brain abscess development,
subsequent analysis focused on MIP-2 and KC/CXCL1, two
neutrophil-attracting CXC chemokines. Both MIP-2 and KC protein levels
were significantly elevated in the brain after S. aureus
exposure. Neutrophil extravasation into the brain parenchyma was
impaired in CXCR2 knockout mice and was associated with increased
bacterial burdens. These studies demonstrate the importance of the
CXCR2 ligands MIP-2 and KC and neutrophils in the acute host response
to S. aureus in the brain.
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