title: Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection.
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.
authors.affiliation: Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Anupam
authors.initials: A
authors.lastname: Jhingran
authors.affiliation: Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kasahara
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth University, Hanover, New Hampshire, United States of America.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Shepardson
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Beth A Fallert
authors.initials: BA
authors.lastname: Junecko
authors.affiliation: Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Lena J
authors.initials: LJ
authors.lastname: Heung
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Debra K
authors.initials: DK
authors.lastname: Kumasaka
authors.affiliation: Comparative Medicine Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Sue E
authors.initials: SE
authors.lastname: Knoblaugh
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Medicine and Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Barbara I
authors.initials: BI
authors.lastname: Kazmierczak
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Reinhart
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth University, Hanover, New Hampshire, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cramer
authors.affiliation: Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America; Immunology Program, Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000502:physiology*; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D055732:Pulmonary Aspergillosis / Q000276:immunology* / Q000382:microbiology; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; D018925:Chemokines; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1