The role of CC chemokine receptor 6 in host defense in a model of invasive pulmonary aspergillosis.
BACKGROUND
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 (DCs) and several lymphocyte subsets to sites of epithelial inflammation, but its role in infections has not been examined extensively.


OBJECTIVE
To test the hypothesis that CCR6-mediated leukocyte recruitment is necessary for effective host defense in neutropenic hosts with invasive pulmonary aspergillosis.


METHODS
Neutropenic wild-type mice 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.


RESULTS
In the context of infection, immature myeloid DCs were the major population of CCR6-expressing cells in the lungs. As compared with wild-type animals, CCR6-deficient mice developed a more severe infection when challenged with A. fumigatus conidia, as documented by a higher mortality rate and greater lung fungal burden. This was associated with reduced accumulation of DCs in the lungs. CCR6-deficient and wild-type DCs did not differ in their phagocytosis of conidia, cytokine response, or maturation in vitro. In adoptive transfer experiments, however, DCs from CCR6-deficient donors showed lesser accumulation in the lungs of infected mice as compared with wild-type cells, and transfer of wild-type, but not CCR6-deficient, DCs resulted in attenuated severity of infection in CCR6-deficient recipients.


CONCLUSIONS
Taken together, these results implicate CCR6-mediated DC influx into the lung in the initial host defense in invasive aspergillosis.
Phadke
Anagha P
AP
Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Akangire
Gangaram
G
Park
Stacy J
SJ
Lira
Sergio A
SA
Mehrad
Borna
B
D000818:Animals; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000378:metabolism* / Q000473:pathology; D001232:Aspergillus fumigatus / Q000472:pathogenicity; D001853:Bone Marrow / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000378:metabolism; D003713:Dendritic Cells / Q000473:pathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007962:Leukocytes / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000502:physiology*; D012720:Severity of Illness Index
C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D054399:Receptors, CCR6; D019707:Receptors, Chemokine