CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment

Rebecca A. Drummond (Corresponding Author), Muthulekha Swamydas, Vasileios Oikonomou, Bing Zhai, Ivy Dambuza, Brian C. Schaefer, Andrea C. Bohrer, Katrin D. Mayer-Barber, Sergio A. Lira, Yoichiro Iwakura, Scott G. Filler, Gordon D. Brown, Bernhard Hube, Julian R. Naglik, Tobias M. Hohl, Michail S. Lionakis (Corresponding Author)

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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 languageEnglish
Pages (from-to)559-570
Number of pages12
JournalNature Immunology
Volume20
Early online date17 Apr 2019
DOIs
Publication statusPublished - May 2019

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

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  • Cite this

    Drummond, R. A., Swamydas, M., Oikonomou, V., Zhai, B., Dambuza, I., Schaefer, B. C., Bohrer, A. C., Mayer-Barber, K. D., Lira, S. A., Iwakura, Y., Filler, S. G., Brown, G. D., Hube, B., Naglik, J. R., Hohl, T. M., & Lionakis, M. S. (2019). CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment. Nature Immunology, 20, 559-570. https://doi.org/10.1038/s41590-019-0377-2