Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection

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 MyD8...

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Bibliographic Details
Published in:PLoS pathogens 2015-01, Vol.11 (1), p.e1004589-e1004589
Main Authors: Jhingran, Anupam, Kasahara, Shinji, Shepardson, Kelly M, Junecko, Beth A Fallert, Heung, Lena J, Kumasaka, Debra K, Knoblaugh, Sue E, Lin, Xin, Kazmierczak, Barbara I, Reinhart, Todd A, Cramer, Robert A, Hohl, Tobias M
Format: Article
Language:English
Subjects:
Adapter proteins
Animals
Aspergillus
Aspergillus fumigatus - physiology
CARD Signaling Adaptor Proteins - metabolism
Chemokines
Chemokines - metabolism
Cytokines
Experiments
Fungal infections
Health aspects
Host-parasite relationships
Humans
Hybridization
Identification and classification
Immunity, Innate
Ligands
Lung - immunology
Lung diseases
Mice
Mice, Knockout
Mortality
Myeloid Differentiation Factor 88 - metabolism
Neutrophil Infiltration - immunology
Neutrophils
Neutrophils - immunology
Physiological aspects
Pulmonary Aspergillosis - immunology
Pulmonary Aspergillosis - microbiology
Receptors, Interleukin-1 - metabolism
Rodents
Signal Transduction
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1004589