Candida albicans triggers NADPH oxidaseindependent neutrophil extracellular traps through dectin-2

Sheng Yang Wu; Chia Lin Weng; Min Jhen Jheng; Hung Wei Kan; Sung Tsang Hsieh; Fu Tong Liu; Betty A. Wu-Hsieh

doi:10.1371/journal.ppat.1008096

Candida albicans triggers NADPH oxidaseindependent neutrophil extracellular traps through dectin-2

Sheng Yang Wu, Chia Lin Weng, Min Jhen Jheng, Hung Wei Kan, Sung Tsang Hsieh, Fu Tong Liu, Betty A. Wu-Hsieh

Research output: Contribution to journal › Article › peer-review

69 Citations (Scopus)

Abstract

Candida albicans is one of the top leading causes of healthcare-Associated bloodstream infection. Neutrophil extracellular traps (NET) are known to capture and kill pathogens. It is reported that opsonized C. albicans-Triggered NETosis is NADPH oxidase-dependent. We discovered a NADPH oxidase-independent NETosis pathway in neutrophil response to unopsonized C. albicans. While CR3 engagement with opsonized C. albicans triggered NET, dectin-2 recognized unopsonized C. albicans and mediated NET formation. Engagement of dectin-2 activated the downstream Syk-Ca²⁺-PKCδ-protein arginine deiminase 4 (PAD4) signaling pathway which modulated nuclear translocation of neutrophil elastase (NE), histone citrullination and NETosis. In a C. albicans peritonitis model we observed Ki67⁺Ly6G⁺ NETotic cells in the peritoneal exudate and mesenteric tissues within 3 h of infection. Treatment with PAD4 inhibitor GSK484 or dectin-2 deficiency reduced % Ki67⁺Ly6G⁺ cells and the intensity of Ki67 in peritoneal neutrophils. Employing DNA digestion enzyme micrococcal nuclease, GSK484 as well as dectin-2-deficient mice, we further showed that dectin-2-mediated PAD4-dependent NET formation in vivo restrained the spread of C. albicans from the peritoneal cavity to kidney. Taken together, this study reveals that unopsonized C. albicans evokes NADPH oxidase-independent NETosis through dectin-2 and its downstream signaling pathway and dectin-2-mediated NET helps restrain fungal dissemination.

Original language	English
Article number	e1008096
Journal	PLoS Pathogens
Volume	15
Issue number	11
DOIs	https://doi.org/10.1371/journal.ppat.1008096
Publication status	Published - 2019
Externally published	Yes

ASJC Scopus subject areas

Parasitology
Microbiology
Immunology
Molecular Biology
Genetics
Virology

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10.1371/journal.ppat.1008096

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@article{ce69eb84eda34369a3b7893288705ebe,

title = "Candida albicans triggers NADPH oxidaseindependent neutrophil extracellular traps through dectin-2",

abstract = "Candida albicans is one of the top leading causes of healthcare-Associated bloodstream infection. Neutrophil extracellular traps (NET) are known to capture and kill pathogens. It is reported that opsonized C. albicans-Triggered NETosis is NADPH oxidase-dependent. We discovered a NADPH oxidase-independent NETosis pathway in neutrophil response to unopsonized C. albicans. While CR3 engagement with opsonized C. albicans triggered NET, dectin-2 recognized unopsonized C. albicans and mediated NET formation. Engagement of dectin-2 activated the downstream Syk-Ca2+-PKCδ-protein arginine deiminase 4 (PAD4) signaling pathway which modulated nuclear translocation of neutrophil elastase (NE), histone citrullination and NETosis. In a C. albicans peritonitis model we observed Ki67+Ly6G+ NETotic cells in the peritoneal exudate and mesenteric tissues within 3 h of infection. Treatment with PAD4 inhibitor GSK484 or dectin-2 deficiency reduced % Ki67+Ly6G+ cells and the intensity of Ki67 in peritoneal neutrophils. Employing DNA digestion enzyme micrococcal nuclease, GSK484 as well as dectin-2-deficient mice, we further showed that dectin-2-mediated PAD4-dependent NET formation in vivo restrained the spread of C. albicans from the peritoneal cavity to kidney. Taken together, this study reveals that unopsonized C. albicans evokes NADPH oxidase-independent NETosis through dectin-2 and its downstream signaling pathway and dectin-2-mediated NET helps restrain fungal dissemination.",

author = "Wu, {Sheng Yang} and Weng, {Chia Lin} and Jheng, {Min Jhen} and Kan, {Hung Wei} and Hsieh, {Sung Tsang} and Liu, {Fu Tong} and Wu-Hsieh, {Betty A.}",

note = "Funding Information: We thank Dr. Gordon Brown (University of Aberdeen, UK) for gift of Clec7a-/- mice and Mihai G. Netea (Radboud University Medical Center, Netherlands) for Clec4n-/- mice. We are grateful to Dr. Chung-Yu Lan (National Tsing Hua University, Taiwan) for the gift of GFPexpressing Candida strain OG1 and Dr. Hsiu-Jung Lo (National Health Research Institutes, Taiwan) for the gift of dTomato-expressing Candida strain CAF2-dTomato. The services provided by the Imaging Core at the First Core Lab of National Taiwan University College of Medicine and the Second Core Lab of Department of Medical Research, National Taiwan University Hospital are gratefully acknowledged. We are grateful to Dr. Michael Hsiao (Genomics Research Center at Academia Sinica, Taiwan) for providing the equipment and technical support for IVIS imaging system. Publisher Copyright: {\textcopyright} 2019 Wu et al.",

year = "2019",

doi = "10.1371/journal.ppat.1008096",

language = "English",

volume = "15",

journal = "PLoS Pathogens",

issn = "1553-7366",

publisher = "Public Library of Science",

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T1 - Candida albicans triggers NADPH oxidaseindependent neutrophil extracellular traps through dectin-2

AU - Wu, Sheng Yang

AU - Weng, Chia Lin

AU - Jheng, Min Jhen

AU - Kan, Hung Wei

AU - Hsieh, Sung Tsang

AU - Liu, Fu Tong

AU - Wu-Hsieh, Betty A.

N1 - Funding Information: We thank Dr. Gordon Brown (University of Aberdeen, UK) for gift of Clec7a-/- mice and Mihai G. Netea (Radboud University Medical Center, Netherlands) for Clec4n-/- mice. We are grateful to Dr. Chung-Yu Lan (National Tsing Hua University, Taiwan) for the gift of GFPexpressing Candida strain OG1 and Dr. Hsiu-Jung Lo (National Health Research Institutes, Taiwan) for the gift of dTomato-expressing Candida strain CAF2-dTomato. The services provided by the Imaging Core at the First Core Lab of National Taiwan University College of Medicine and the Second Core Lab of Department of Medical Research, National Taiwan University Hospital are gratefully acknowledged. We are grateful to Dr. Michael Hsiao (Genomics Research Center at Academia Sinica, Taiwan) for providing the equipment and technical support for IVIS imaging system. Publisher Copyright: © 2019 Wu et al.

PY - 2019

Y1 - 2019

N2 - Candida albicans is one of the top leading causes of healthcare-Associated bloodstream infection. Neutrophil extracellular traps (NET) are known to capture and kill pathogens. It is reported that opsonized C. albicans-Triggered NETosis is NADPH oxidase-dependent. We discovered a NADPH oxidase-independent NETosis pathway in neutrophil response to unopsonized C. albicans. While CR3 engagement with opsonized C. albicans triggered NET, dectin-2 recognized unopsonized C. albicans and mediated NET formation. Engagement of dectin-2 activated the downstream Syk-Ca2+-PKCδ-protein arginine deiminase 4 (PAD4) signaling pathway which modulated nuclear translocation of neutrophil elastase (NE), histone citrullination and NETosis. In a C. albicans peritonitis model we observed Ki67+Ly6G+ NETotic cells in the peritoneal exudate and mesenteric tissues within 3 h of infection. Treatment with PAD4 inhibitor GSK484 or dectin-2 deficiency reduced % Ki67+Ly6G+ cells and the intensity of Ki67 in peritoneal neutrophils. Employing DNA digestion enzyme micrococcal nuclease, GSK484 as well as dectin-2-deficient mice, we further showed that dectin-2-mediated PAD4-dependent NET formation in vivo restrained the spread of C. albicans from the peritoneal cavity to kidney. Taken together, this study reveals that unopsonized C. albicans evokes NADPH oxidase-independent NETosis through dectin-2 and its downstream signaling pathway and dectin-2-mediated NET helps restrain fungal dissemination.

AB - Candida albicans is one of the top leading causes of healthcare-Associated bloodstream infection. Neutrophil extracellular traps (NET) are known to capture and kill pathogens. It is reported that opsonized C. albicans-Triggered NETosis is NADPH oxidase-dependent. We discovered a NADPH oxidase-independent NETosis pathway in neutrophil response to unopsonized C. albicans. While CR3 engagement with opsonized C. albicans triggered NET, dectin-2 recognized unopsonized C. albicans and mediated NET formation. Engagement of dectin-2 activated the downstream Syk-Ca2+-PKCδ-protein arginine deiminase 4 (PAD4) signaling pathway which modulated nuclear translocation of neutrophil elastase (NE), histone citrullination and NETosis. In a C. albicans peritonitis model we observed Ki67+Ly6G+ NETotic cells in the peritoneal exudate and mesenteric tissues within 3 h of infection. Treatment with PAD4 inhibitor GSK484 or dectin-2 deficiency reduced % Ki67+Ly6G+ cells and the intensity of Ki67 in peritoneal neutrophils. Employing DNA digestion enzyme micrococcal nuclease, GSK484 as well as dectin-2-deficient mice, we further showed that dectin-2-mediated PAD4-dependent NET formation in vivo restrained the spread of C. albicans from the peritoneal cavity to kidney. Taken together, this study reveals that unopsonized C. albicans evokes NADPH oxidase-independent NETosis through dectin-2 and its downstream signaling pathway and dectin-2-mediated NET helps restrain fungal dissemination.

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Candida albicans triggers NADPH oxidaseindependent neutrophil extracellular traps through dectin-2

Abstract

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