The Role of CC Chemokine Receptor 7 During Pulmonary Invasive Aspergillosis.

Abstract

Invasive aspergillosis (IA) is a serious, life-threatening disease caused by the mold Aspergillus fumigatus (A. fumigatus). IA primarily affects immunocompromised individuals, and is especially common among hematopoietic stem cell transplantation (HSCT) patients. Immune strategies directed at promoting antifungal responses following HSCT hold promise. In particular, alteration of chemokines and their receptors have been shown to markedly modulate the immune response against A. fumigatus. Examples include chemokine receptor 1 (CCR1), CCR2, CCR4, CCR6, CXCR2, and their associated chemokine ligands. However, more recently it was shown that Aspergillus infection upregulates CC chemokine receptor 7 (CCR7) expression on dendritic cells, a major effector cell mediating antifungal immune responses in the lung. CCR7 via activation by chemokine ligand 19 (CCL19) and chemokine ligand 21 (CCL21) is a key trafficking receptor found on naïve lymphocytes and mature dendritic cells. In addition, CCR7 gene transcripts are found in hematopoietic stem cells and myeloid progenitor cells. Given the role of CCR7 for immune cell trafficking, we hypothesized that CCR7 would be an important chemokine receptor during IA. To test our hypothesis, we utilized two distinct murine models of immunosuppression. In our first model, we describe a potentially deleterious role for CCR7 during primary immune responses directed against A. fumigatus following antibody-induced neutropenia. CCR7-deficient chimeric mice displayed significantly reduced mortality, which correlated with rapid fungal clearance and increased effector responses by myeloid dendritic cells compared to wild-type chimeras. In our second model, we demonstrate a novel inhibitory role for CCR7 on hematopoietic stem cell and myeloid progenitor cell proliferation following HSCT. Mice reconstituted with CCR7-deficient hematopoietic stem cells and myeloid progenitors had greater numbers of immune cells in the lung 14 days after transplantation, compared with mice receiving wild-type hematopoietic stem cells and myeloid progenitors, and this resulted in accelerated fungal clearance in A. fumigatus challenged mice. Collectively, our results demonstrate a detrimental role for CCR7 during primary immune responses against A. fumigatus and following HSCT, and suggest CCR7 as a new target for the treatment and prevention of IA.Ph.D.ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/63754/1/ajhart_1.pd