Candida albicans triggers NADPH oxidase-independent 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 journalArticle

2 Scopus citations

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 languageEnglish (US)
Pages (from-to)e1008096
JournalPLoS pathogens
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2019

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ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Wu, S. Y., Weng, C. L., Jheng, M. J., Kan, H. W., Hsieh, S. T., Liu, F. T., & Wu-Hsieh, B. A. (2019). Candida albicans triggers NADPH oxidase-independent neutrophil extracellular traps through dectin-2. PLoS pathogens, 15(11), e1008096. https://doi.org/10.1371/journal.ppat.1008096