CARD9
Animals
Brain
/ immunology
CARD Signaling Adaptor Proteins
/ genetics
Candida albicans
/ immunology
Candidiasis
/ genetics
Chemokine CXCL1
/ genetics
Cytokines
/ genetics
Host-Pathogen Interactions
/ immunology
Inflammasomes
/ genetics
Interleukin-1beta
/ genetics
Mice, Knockout
Mice, Transgenic
Microglia
/ immunology
Neutrophil Infiltration
/ genetics
Neutrophils
/ immunology
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
25
05
2018
accepted:
12
03
2019
entrez:
19
4
2019
pubmed:
19
4
2019
medline:
30
4
2019
Statut:
ppublish
Résumé
The C-type lectin receptor-Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans. The cytokine IL-1β served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1β and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1β, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1β and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host-pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS.
Identifiants
pubmed: 30996332
doi: 10.1038/s41590-019-0377-2
pii: 10.1038/s41590-019-0377-2
pmc: PMC6494474
mid: NIHMS1523856
doi:
Substances chimiques
CARD Signaling Adaptor Proteins
0
Card9 protein, mouse
0
Chemokine CXCL1
0
Cxcl1 protein, mouse
0
Cytokines
0
Inflammasomes
0
Interleukin-1beta
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
559-570Subventions
Organisme : NIDCR NIH HHS
ID : R01 DE026600
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI093808
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA161373
Pays : United States
Organisme : NIH HHS
ID : R01AI124566
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : Medical Research Council
ID : MR/N006364/1
Pays : United Kingdom
Organisme : NIH HHS
ID : R01 093808
Pays : United States
Organisme : NIH HHS
ID : R01CA161373
Pays : United States
Organisme : Medical Research Council
ID : MR/N006364/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M011372/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 102705/Z/13/Z
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK110352
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI124566
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AI001175-01
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE017088
Pays : United States
Commentaires et corrections
Type : CommentIn
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