CARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system Journal Article

Authors: Drummond, R. A.; Collar, A. L.; Swamydas, M.; Rodríguez, C. A.; Lim, J. K.; Mendez, L. M.; Fink, D. L.; Hsu, A. P.; Zhai, B.; Karauzum, H.; Mikelis, C. M.; Rose, S. R.; Ferre, E. M. N.; Yockey, L.; Lemberg, K.; Kuehn, H. S.; Rosenzweig, S. D.; Lin, X.; Chittiboina, P.; Datta, S. K.; Belhorn, T. H.; Weimer, E. T.; Hernandez, M. L.; Hohl, T. M.; Kuhns, D. B.; Lionakis, M. S.
Article 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. © 2015, Public Library of Science, All Rights Reserved.
Keywords: controlled study; human tissue; protein expression; unclassified drug; human cell; missense mutation; histopathology; neutropenia; nonhuman; reverse transcription polymerase chain reaction; interleukin 8; transcription factor; chemokine; western blotting; cell migration; cytokine production; protein deficiency; staphylococcus infection; cell adhesion; fluorescence activated cell sorting; fluconazole; candidiasis; chemoattractant; neutrophil chemotaxis; lipocortin 5; central nervous system infection; ionomycin; osteomyelitis; meningoencephalitis; human; article; card9 protein; 7-aad assay; parasite load
Journal Title: PLoS Pathogens
Volume: 11
Issue: 12
ISSN: 1553-7366
Publisher: Public Library of Science  
Date Published: 2015-12-17
Start Page: e1005293
Language: English
DOI: 10.1371/journal.ppat.1005293
PROVIDER: scopus
PMCID: PMC4683065
PUBMED: 26679537
Notes: Article -- Export Date: 3 February 2016 -- Source: Scopus
Citation Impact
MSK Authors
  1. Tobias Martin Hohl
    76 Hohl
  2. Bing   Zhai
    8 Zhai