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)

Research output: Contribution to journalArticle

8 Citations (Scopus)

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

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Neutrophil Infiltration
Microglia
Interleukin-1
Immunity
Central Nervous System
Neutrophils
Inflammasomes
C-Type Lectins
Host-Pathogen Interactions
Central Nervous System Infections
Fungal Proteins
Mycoses
Central Nervous System Diseases
Candida albicans

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Drummond, R. A., Swamydas, M., Oikonomou, V., Zhai, B., Dambuza, I., Schaefer, B. C., ... 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

CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment. / Drummond, Rebecca A. (Corresponding Author); Swamydas, Muthulekha; Oikonomou, Vasileios; Zhai, Bing; Dambuza, Ivy; Schaefer, Brian C.; Bohrer, Andrea C.; Mayer-Barber, Katrin D.; Lira, Sergio A.; Iwakura, Yoichiro; Filler, Scott G.; Brown, Gordon D.; Hube, Bernhard; Naglik, Julian R.; Hohl, Tobias M.; Lionakis, Michail S. (Corresponding Author).

In: Nature Immunology, Vol. 20, 05.2019, p. 559-570.

Research output: Contribution to journalArticle

Drummond, RA, Swamydas, M, Oikonomou, V, Zhai, B, Dambuza, I, Schaefer, BC, Bohrer, AC, Mayer-Barber, KD, Lira, SA, Iwakura, Y, Filler, SG, Brown, GD, Hube, B, Naglik, JR, Hohl, TM & Lionakis, MS 2019, 'CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment', Nature Immunology, vol. 20, pp. 559-570. https://doi.org/10.1038/s41590-019-0377-2
Drummond, Rebecca A. ; Swamydas, Muthulekha ; Oikonomou, Vasileios ; Zhai, Bing ; Dambuza, Ivy ; Schaefer, Brian C. ; Bohrer, Andrea C. ; Mayer-Barber, Katrin D. ; Lira, Sergio A. ; Iwakura, Yoichiro ; Filler, Scott G. ; Brown, Gordon D. ; Hube, Bernhard ; Naglik, Julian R. ; Hohl, Tobias M. ; Lionakis, Michail S. / CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment. In: Nature Immunology. 2019 ; Vol. 20. pp. 559-570.
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title = "CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment",
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.",
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",
author = "Drummond, {Rebecca A.} and Muthulekha Swamydas and Vasileios Oikonomou and Bing Zhai and Ivy Dambuza and Schaefer, {Brian C.} and Bohrer, {Andrea C.} and Mayer-Barber, {Katrin D.} and Lira, {Sergio A.} and Yoichiro Iwakura and Filler, {Scott G.} and Brown, {Gordon D.} and Bernhard Hube and Naglik, {Julian R.} and Hohl, {Tobias M.} and Lionakis, {Michail S.}",
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.",
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T1 - CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment

AU - Drummond, Rebecca A.

AU - Swamydas, Muthulekha

AU - Oikonomou, Vasileios

AU - Zhai, Bing

AU - Dambuza, Ivy

AU - Schaefer, Brian C.

AU - Bohrer, Andrea C.

AU - Mayer-Barber, Katrin D.

AU - Lira, Sergio A.

AU - Iwakura, Yoichiro

AU - Filler, Scott G.

AU - Brown, Gordon D.

AU - Hube, Bernhard

AU - Naglik, Julian R.

AU - Hohl, Tobias M.

AU - Lionakis, Michail S.

N1 - 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.

PY - 2019/5

Y1 - 2019/5

N2 - 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.

AB - 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.

KW - Animals

KW - Brain/immunology

KW - CARD Signaling Adaptor Proteins/genetics

KW - Candida albicans/immunology

KW - Candidiasis/genetics

KW - Chemokine CXCL1/genetics

KW - Cytokines/genetics

KW - Host-Pathogen Interactions/immunology

KW - Inflammasomes/genetics

KW - Interleukin-1beta/genetics

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Microglia/immunology

KW - Neutrophil Infiltration/genetics

KW - Neutrophils/immunology

KW - ACTIVATION

KW - SUSCEPTIBILITY

KW - ASPARTYL PROTEINASES

KW - CENTRAL-NERVOUS-SYSTEM

KW - INFLAMMATORY MONOCYTES

KW - ASTROCYTES

KW - DEFICIENCY

KW - HOST PROTECTION

KW - FUNGAL-INFECTIONS

KW - CELL

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UR - http://www.mendeley.com/research/card9-microglia-promote-antifungal-immunity-via-il1%CE%B2-cxcl1mediated-neutrophil-recruitment

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JF - Nature Immunology

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