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

• Published in: PLoS pathogens Vol. 15; no. 11; p. e1008096
• Main Authors: Wu, Sheng-Yang, Weng, Chia-Lin, Jheng, Min-Jhen, Kan, Hung-Wei, Hsieh, Sung-Tsang, Liu, Fu-Tong, Wu-Hsieh, Betty A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.11.2019; Public Library of Science (PLoS)
• Subjects: Animals; Arginine; Arginine deiminase; Biology and Life Sciences; Calcium; Calcium ions; Candida albicans; Candida albicans - immunology; Candidiasis - immunology; Candidiasis - metabolism; Candidiasis - microbiology; Cell cycle; Citrulline; Deoxyribonucleic acid; DNA; Elastase; Enzymes; Extracellular Traps - immunology; Exudation; Health aspects; Immunology; Infection; Infections; Kidney - immunology; Kidney - metabolism; Kidneys; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Leukocytes (neutrophilic); Medical schools; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; NAD(P)H oxidase; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Neutrophils; Nuclear transport; Nuclease; Nucleases; Opsonization; Oxidase; Oxidases; Pathogenic microorganisms; Peritoneum; Peritoneum - immunology; Peritoneum - metabolism; Peritonitis; Phagocytosis; Protein kinase C; Reactive Oxygen Species; Research and Analysis Methods; Signal Transduction; Signaling; Software; Supervision; Syk protein; Translocation; Taiwan
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008096

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.