Date Published: February 20, 2014
Publisher: Public Library of Science
Author(s): Vanessa Espinosa, Anupam Jhingran, Orchi Dutta, Shinji Kasahara, Robert Donnelly, Peicheng Du, Jeffrey Rosenfeld, Ingrid Leiner, Chiann-Chyi Chen, Yacov Ron, Tobias M. Hohl, Amariliz Rivera, Don C. Sheppard.
Aspergillus fumigatus is an environmental fungus that causes invasive aspergillosis (IA) in immunocompromised patients. Although -CC-chemokine receptor-2 (CCR2) and Ly6C-expressing inflammatory monocytes (CCR2+Mo) and their derivatives initiate adaptive pulmonary immune responses, their role in coordinating innate immune responses in the lung remain poorly defined. Using conditional and antibody-mediated cell ablation strategies, we found that CCR2+Mo and monocyte-derived dendritic cells (Mo-DCs) are essential for innate defense against inhaled conidia. By harnessing fluorescent Aspergillus reporter (FLARE) conidia that report fungal cell association and viability in vivo, we identify two mechanisms by which CCR2+Mo and Mo-DCs exert innate antifungal activity. First, CCR2+Mo and Mo-DCs condition the lung inflammatory milieu to augment neutrophil conidiacidal activity. Second, conidial uptake by CCR2+Mo temporally coincided with their differentiation into Mo-DCs, a process that resulted in direct conidial killing. Our findings illustrate both indirect and direct functions for CCR2+Mo and their derivatives in innate antifungal immunity in the lung.
The incidence of fungal infections has been on the rise for several decades due to increased use of immunosuppressive and myeloablative therapies for malignant and non-malignant diseases , , . Invasive aspergillosis (IA), most commonly caused by A. fumigatus, is a frequent cause of infectious morbidity and mortality in patients with leukemia and in allogeneic hematopoietic cell transplant (HCT) recipients , , , .
In this study, we uncover novel and essential functions for CCR2+ inflammatory monocytes and their derivative Mo-DCs in innate antifungal defense in the lung. The protective role of CCR2+Mo and their derivatives against A. fumigatus is not compensated by neutrophil antifungal activity. Similarly, our findings confirm the long-standing tenet that neutrophil function is essential for host defense against IA , , , . Thus, CCR2+Mo and derivative Mo-DC as well as neutrophils represent essential innate immune cells that prevent the formation of tissue-invasive hyphae and IA in the murine lung. In contrast, NK cells and other common gamma chain-dependent innate lymphocyte populations were not essential to mediate innate defense against inhaled A. fumigatus conidia, since mice deficient in these leukocyte populations contained conidial germination and did not develop invasive disease.