title: CARD9-Dependent Neutrophil Recruitment Protects against Fungal Invasion of the Central Nervous System.
abstract: Candida is the most common human fungal pathogen and causes systemic infections that require neutrophils for effective host defense. Humans deficient in the C-type lectin pathway adaptor protein CARD9 develop spontaneous fungal disease that targets the central nervous system (CNS). However, how CARD9 promotes protective antifungal immunity in the CNS remains unclear. Here, we show that a patient with CARD9 deficiency had impaired neutrophil accumulation and induction of neutrophil-recruiting CXC chemokines in the cerebrospinal fluid despite uncontrolled CNS Candida infection. We phenocopied the human susceptibility in Card9-/- mice, which develop uncontrolled brain candidiasis with diminished neutrophil accumulation. The induction of neutrophil-recruiting CXC chemokines is significantly impaired in infected Card9-/- brains, from both myeloid and resident glial cellular sources, whereas cell-intrinsic neutrophil chemotaxis is Card9-independent. Taken together, our data highlight the critical role of CARD9-dependent neutrophil trafficking into the CNS and provide novel insight into the CNS fungal susceptibility of CARD9-deficient humans.
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Drummond
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Collar
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Muthulekha
authors.initials: M
authors.lastname: Swamydas
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rodriguez
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Jean K
authors.initials: JK
authors.lastname: Lim
authors.affiliation: Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Mendez
authors.affiliation: Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Fink
authors.affiliation: Immunopathogenesis Section, LCID, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.affiliation: Infectious Disease Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhai
authors.affiliation: Bacterial Pathogenesis Unit, LCID, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Hatice
authors.initials: H
authors.lastname: Karauzum
authors.affiliation: Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America.
authors.forename: Constantinos M
authors.initials: CM
authors.lastname: Mikelis
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Rose
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Elise M N
authors.initials: EM
authors.lastname: Ferre
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Lynne
authors.initials: L
authors.lastname: Yockey
authors.affiliation: Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, United States of America.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lemberg
authors.affiliation: Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, United States of America.
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Kuehn
authors.affiliation: Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, United States of America.
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Rosenzweig
authors.affiliation: Department of Molecular and Cellular Oncology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, United States of America.
authors.forename: Prashant
authors.initials: P
authors.lastname: Chittiboina
authors.affiliation: Bacterial Pathogenesis Unit, LCID, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Datta
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Belhorn
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Weimer
authors.affiliation: Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hernandez
authors.affiliation: Infectious Disease Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
authors.affiliation: Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Michail S
authors.initials: MS
authors.lastname: Lionakis
mesh_terms: D000818:Animals; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology*; D002494:Central Nervous System Infections / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology*
chemical_list: D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; C513280:Card9 protein, mouse