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Is a Critical Mediator of Host Defense Against Invasive Pulmonary Aspergillosis in Neutropenic Hosts
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109
Invasive pulmonary aspergillosis is a devastating complication of
immunosuppression that usually occurs in neutropenic patients. In this
setting, augmentation of the antifungal activity of available immune
cells may improve the outcome of the infection. Macrophage inflammatory
protein-1
(MIP-1) is a CC chemokine with potent chemotactic
activity for various subsets of mononuclear leukocytes. We therefore
tested the hypothesis that the influx of mononuclear cells into the
lung in invasive pulmonary aspergillosis is in part mediated by
MIP-1, and the manipulation of this ligand alters the outcome of the
infection. We found that in both immunocompetent and neutropenic mice,
MIP-1 was induced in the lungs in response to intratracheal
administration of Aspergillus fumigatus conidia. In
neutrophil-depleted mice challenged with intratracheal conidia, there
was evidence of invasive fungal pneumonia associated with a
predominantly mononuclear leukocyte infiltrate. Ab-mediated depletion
of MIP-1 resulted in a 6-fold increase in mortality in neutropenic
mice, which was associated with a 12-fold increase in lung fungal
burden. Studies of single-cell suspensions of whole lungs revealed a
36% decrease in total lung leukocyte infiltration as a result of
MIP-1 neutralization. Flow cytometry on whole lung suspensions
showed a 41% reduction in lung monocyte/macrophages as a result of
MIP-1 neutralization, but no difference in other lung leukocyte
subsets. These studies indicate that MIP-1 is a critical mediator of
host defense against A. fumigatus in the setting of
neutropenia and may be an important target in devising future
therapeutic strategies against invasive
aspergillosis.
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