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

doi:10.1038/s41590-019-0377-2

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

Immunology and Immunotherapy

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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 language	English
Pages (from-to)	559–570
Number of pages	12
Journal	Nature Immunology
Volume	20
Issue number	5
Early online date	17 Apr 2019
DOIs	https://doi.org/10.1038/s41590-019-0377-2
Publication status	Published - May 2019

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Cite this

Drummond, R. A., Swamydas, M., Oikonomou, V., Zhai, B., Dambuza, I. M., 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 Orchestrate Antifungal Immunity via IL-1β and CXCL1-mediated Neutrophil Recruitment. Nature Immunology, 20(5), 559–570. https://doi.org/10.1038/s41590-019-0377-2

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title = "CARD9+ Microglia Orchestrate 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. 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. ",

author = "Drummond, {Rebecca A.} and Muthulekha Swamydas and Vasileios Oikonomou and Bing Zhai and Dambuza, {Ivy M.} 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.}",

year = "2019",

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doi = "10.1038/s41590-019-0377-2",

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Drummond, RA, Swamydas, M, Oikonomou, V, Zhai, B, Dambuza, IM, 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 Orchestrate Antifungal Immunity via IL-1β and CXCL1-mediated Neutrophil Recruitment', Nature Immunology, vol. 20, no. 5, pp. 559–570. https://doi.org/10.1038/s41590-019-0377-2

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T1 - CARD9+ Microglia Orchestrate 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 M.

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.

PY - 2019/5

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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. 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.

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. 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.

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DO - 10.1038/s41590-019-0377-2

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SN - 1529-2908

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JO - Nature Immunology

JF - Nature Immunology

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