Candida albicans triggers NADPH oxidase-independent neutrophil extracellular traps through dectin-2

PLoS Pathog. 2019 Nov 6;15(11):e1008096. doi: 10.1371/journal.ppat.1008096. eCollection 2019 Nov.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Candida albicans / immunology*
  • Candidiasis / immunology*
  • Candidiasis / metabolism
  • Candidiasis / microbiology
  • Extracellular Traps / immunology*
  • Kidney / immunology*
  • Kidney / metabolism
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • Peritoneum / immunology*
  • Peritoneum / metabolism
  • Phagocytosis
  • Reactive Oxygen Species
  • Signal Transduction

Substances

  • Lectins, C-Type
  • Reactive Oxygen Species
  • dectin-2, mouse
  • NADPH Oxidases

Grant support

This work was supported by Academia Sinica (https://www.sinica.edu.tw) thematic project AS-105-TP-B08 to BWH and the Ministry of Science and Technology (http://www.most.gov.tw) research grants 104-2320-B-002-052-MY2 and 106-2321-B- 002-003 to BWH, and 107-2321-B-002-053-MY3 to SYW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.