The Role of CC Chemokine Receptor-6 in Host Defense in a Model of Invasive Pulmonary Aspergillosis
Author:
Phadke AP, Akangire G, Park SJ, Lira SA, Mehrad B
Date: 20 April 2007
Abstract:
RATIONALE: Invasive aspergillosis is a severe fungal infection afflicting immunocompromised patients, particularly patients with neutrophil defects. CCR6, a beta-chemokine receptor, mediates migration of dendritic cells and several lymphocyte subsets to sites of epithelial inflammation, but its role in infections has not been examined extensively. !
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!OBJECTIVE: To test the hypothesis that CCR6-mediated leukocyte recruitment is necessary for effective host defense in neutropenic hosts with invasive pulmonary aspergillosis. !
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!METHODS: Neutropenic wildtype and mice with targeted deletion of CCR6 were infected with Aspergillus fumigatus. The host responses to the infection were compared in vivo and leukocyte responses to the fungus were examined in vitro. !
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!MEASUREMENTS AND MAIN RESULTS: In the context of infection, immature myeloid dendritic cells were the major population of CCR6-expressing cells in the lungs. As compared to wildtype animals, CCR6-deficient mice developed a more severe infection when challenged with Aspergillus fumigatus conidia, as documented by a higher mortality rate and greater lung fungal burden. This was associated with reduced accumulation of dendritic cells in the lungs. CCR6-deficient and wildtype dendritic cells did not differ in their phagocytosis of conidia, cytokine response, or maturation in vitro. In adoptive transfer experiments, however, dendritic cells from CCR6-deficient donors showed lesser accumulation in the lungs of infected mice as compared to wildtype cells, and transfer of wildtype, but not CCR6-deficient, dendritic cells resulted in attenuated severity of infection in CCR6-deficient recipients. !
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!CONCLUSIONS: Taken together, these results implicate CCR6-mediated dendritic cell influx into the lung in the initial host defense in invasive aspergillosis.
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