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

• DOI: 10.1371/journal.ppat.1004589
• Publication Date: 2015-01-26T19:07:39Z
• Authors: Anupam Jhingran; Shinji Kasahara; Kelly M. Shepardson; Beth A. Fallert J...; Lena J. Heung; Debra K. Kumasaka; Sue E. Knoblaugh; Xin Lin; Barbara I. Kazmie...; Todd A. Reinhart; Robert A. Cramer; Tobias M. Hohl
• Keywords: CXCL2; CXCL1; Neutrophil elastase

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, interleukin-1 family receptor signals, defining temporal spatial pattern of MyD88- CARD9-coupled signals in immune activation clearance has been difficult to achieve. Herein, we demonstrate act two discrete phases cellular compartments direct chemokine- neutrophil-dependent host defense. The first phase depends signaling because genetic deletion leads delayed induction neutrophil chemokines CXCL1 CXCL5, lung trafficking, fatal pulmonary damage at onset infection. expression epithelial cells restores rapid chemokine recruitment signaling. Exogenous administration reverses murine mortality MyD88-deficient mice. second predominately radiosensitive hematopoietic interrupts CXCL2 production beyond initial MyD88-dependent phase. Using reporter mouse, show lung-infiltrating neutrophils represent major source during CARD9-dependent recruitment. neutrophil-intrinsic function are dispensable for conidial uptake killing lung, global both triggers rapidly progressive invasive disease when mice challenged with an inoculum is sub-lethal single adapter protein knockout Our findings distinct signal transduction pathways epithelium compartment partially overlap ensure optimal induction, recruitment, within tract.