Abstract
Aspergillus fumigatus forms ubiquitous airborne conidia that humans inhale on a daily basis. Although respiratory fungal infection activates the adaptor proteins CARD9 and MyD88 via C-type lectin, Toll-like, and interleukin-1 family receptor signals, defining the temporal and spatial pattern of MyD88- and CARD9-coupled signals in immune activation and fungal clearance has been difficult to achieve. Herein, we demonstrate that MyD88 and CARD9 act in two discrete phases and in two cellular compartments to direct chemokine- and neutrophil-dependent host defense. The first phase depends on MyD88 signaling because genetic deletion of MyD88 leads to delayed induction of the neutrophil chemokines CXCL1 and CXCL5, delayed neutrophil lung trafficking, and fatal pulmonary damage at the onset of respiratory fungal infection. MyD88 expression in lung epithelial cells restores rapid chemokine induction and neutrophil recruitment via interleukin-1 receptor signaling. Exogenous CXCL1 administration reverses murine mortality in MyD88-deficient mice. The second phase depends predominately on CARD9 signaling because genetic deletion of CARD9 in radiosensitive hematopoietic cells interrupts CXCL1 and CXCL2 production and lung neutrophil recruitment beyond the initial MyD88-dependent phase. Using a CXCL2 reporter mouse, we show that lung-infiltrating neutrophils represent the major cellular source of CXCL2 during CARD9-dependent recruitment. Although neutrophil-intrinsic MyD88 and CARD9 function are dispensable for neutrophil conidial uptake and killing in the lung, global deletion of both adaptor proteins triggers rapidly progressive invasive disease when mice are challenged with an inoculum that is sub-lethal for single adapter protein knockout mice. Our findings demonstrate that distinct signal transduction pathways in the respiratory epithelium and hematopoietic compartment partially overlap to ensure optimal chemokine induction, neutrophil recruitment, and fungal clearance within the respiratory tract.
Highlights
Aspergillus fumigatus is a leading cause of infectious morbidity and mortality in patients with hematologic malignancies, allogeneic stem cell transplant recipients and in patients receiving immune suppressive therapies [1,2]
Host defense against A. fumigatus involves the activation of two host signal transducers, MyD88 and CARD9, leading to neutrophil recruitment to the infection site
The second phase of neutrophil recruitment is initiated by CARD9 signaling in hematopoietic cells
Summary
Aspergillus fumigatus is a leading cause of infectious morbidity and mortality in patients with hematologic malignancies, allogeneic stem cell transplant recipients and in patients receiving immune suppressive therapies [1,2]. Airborne conidia (asexual spores) represent the infectious propagules that humans inhale daily. Due to their small size (*2–3 μm diameter), conidia can bypass mucociliary clearance and reach terminal airways [3,4]. Antibody-mediated blockade [8] or genetic deficiency of the chemokine receptor CXCR2 [7] results in delayed neutrophil airway recruitment and the development of invasive aspergillosis (IA). Consistent with this notion, overexpression of a CXCR2 ligand (i.e. CXCL1/KC) in the murine lung improves outcomes in neutropenic mice infected with A. fumigatus [9]
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