Compartment-Specific and Sequential Role of MyD88 and CARD9 in Chemokine Induction and Innate Defense during Respiratory Fungal Infection

PLoS Pathogens

Sue E. Knoblaugh¹  Todd A. Reinhart²  Beth A. Fallert Junecko²  Barbara I. Kazmierczak³  Kelly M. Shepardson⁴  Robert A. Cramer⁴  Xin Lin⁵  Debra K. Kumasaka⁶  Lena J. Heung⁷  Anupam Jhingran⁷  Shinji Kasahara⁷  Tobias M. Hohl⁷ 

[1] Comparative Medicine Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America;Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America;Department of Medicine and Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, United States of America;Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth University, Hanover, New Hampshire, United States of America;Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America;Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America;Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America

关键词: Neutrophils;    Chemokines;    Aspergillus fumigatus;    Respiratory infections;    Respiratory physiology;    Fungal diseases;    Immune receptor signaling;    Epithelial cells;   

DOI  :  10.1371/journal.ppat.1004589

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY