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

Research output: Contribution to journalArticle

Authors

  • 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

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)559–570
Number of pages12
JournalNature Immunology
Volume20
Issue number5
Early online date17 Apr 2019
Publication statusPublished - May 2019