Abstract
The C-type lectin receptor/Syk adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human CARD9-deficiency causes fungal-specific CNS-targeted infection susceptibility. We previously showed that CARD9 is required for neutrophil recruitment to the fungal-infected CNS, which mediates fungal clearance. Here, we investigated host and pathogen factors that promote protective neutrophil recruitment during Candida albicans CNS invasion and examined their dependence on CARD9 for in vivo induction. We show that IL-1b is essential for CNS antifungal immunity by driving CXCL1 production, which recruits CXCR2-expressing neutrophils. Neutrophil-recruiting IL-1b and CXCL1 production is induced in microglia by the fungal-secreted peptide toxin Candidalysin, in a p38-cFos-dependent manner. Importantly, microglia rely on CARD9 for production of IL-1b, via both pro-IL-1b transcriptional regulation and inflammasome activation, and of CXCL1 in the fungal-infected CNS, and we show that microglia-specific CARD9 deletion impairs IL40 1b and CXCL1 production and neutrophil recruitment, and increases CNS fungal proliferation. Our data reveals an intricate network of host-pathogen interactions that promotes CNS antifungal immunity and provides novel mechanistic insights into how human CARD9-deficiency causes CNS fungal disease.
Original language | English |
---|---|
Pages (from-to) | 559-570 |
Number of pages | 12 |
Journal | Nature Immunology |
Volume | 20 |
Early online date | 17 Apr 2019 |
DOIs | |
Publication status | Published - May 2019 |
Bibliographical note
This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, National Institutes of Health, as well as NIH grants awarded to TMH (R01 093808), SGF (R01AI124566) and SRL (R01CA161373). Additional funding was provided by the Burroughs Wellcome Fund (awarded to TMH), the Wellcome Trust (102705, 097377; awarded to GDB), the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1; awarded to GDB). The authors additionally thank Celeste Huaman for care and screening of the Malt1 793 -/- mice.Keywords
- 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
- ACTIVATION
- SUSCEPTIBILITY
- ASPARTYL PROTEINASES
- CENTRAL-NERVOUS-SYSTEM
- INFLAMMATORY MONOCYTES
- ASTROCYTES
- DEFICIENCY
- HOST PROTECTION
- FUNGAL-INFECTIONS
- CELL