CARD9+ Microglia Orchestrate Antifungal Immunity via IL-1β and CXCL1-mediated Neutrophil Recruitment

Rebecca A. Drummond, Muthulekha Swamydas, Vasileios Oikonomou, Bing Zhai, Ivy M. 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

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)
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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. 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. IL-1β was essential for CNS antifungal immunity by driving CXCL1 production, which recruited CXCR2-expressing neutrophils. Neutrophil-recruiting IL-1β and CXCL1 production was induced in microglia by the fungal-secreted toxin Candidalysin, in a p38-cFos-dependent manner. Importantly, microglia relied on CARD9 for production of IL-1β, via both Il1b transcriptional regulation and inflammasome activation, and of CXCL1 in the fungal-infected CNS. Microglia-specific Card9 deletion impaired IL-1β and CXCL1 production and neutrophil recruitment, and increased CNS fungal proliferation. Taken together, an intricate network of host-pathogen interactions promotes CNS antifungal immunity, which is impaired in human CARD9-deficiency leading to CNS fungal disease.
Original languageEnglish
Pages (from-to)559–570
Number of pages12
JournalNature Immunology
Volume20
Issue number5
Early online date17 Apr 2019
DOIs
Publication statusPublished - May 2019

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