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- Title
Candida albicans triggers NADPH oxidase-independent neutrophil extracellular traps through dectin-2.
- Authors
Wu, Sheng-Yang; Weng, Chia-Lin; Jheng, Min-Jhen; Kan, Hung-Wei; Hsieh, Sung-Tsang; Liu, Fu-Tong; Wu-Hsieh, Betty A.
- 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 summary: Candida albicans as a dimorphic fungal pathogen is one of the top leading causes of overall healthcare-associated bloodstream infection worldwide. Invasive candidiasis affects more than 250,000 people each year and leads to more than 50,000 deaths. Upon stimulation, neutrophils release nuclear DNA that forms a web-like structure named neutrophil extracellular traps (NET). NET is known to capture pathogens and restrain the spread of infection in the host. It has been reported that opsonized C. albicans induces NET through NADPH oxidase. Here we show a NADPH oxidase-independent NETosis in response to unopsonized C. albicans. Signaling pathway leading to NETosis involves dectin-2 downstream Syk-Ca2+-PKCδ-PAD4/NE. In a C. albicans peritonitis model, NETotic cells are found in the peritoneal exudates and they adhere to mesenteric tissue. Treatment with PAD4 inhibitor or dectin-2 deficiency dampens the ability of neutrophil to undergo NETosis and facilitates the spread of fungus from the peritoneal cavity to kidney. Our work defines the molecular mechanism involved in NADPH oxidase-independent NET formation and sheds light on the role of dectin-2 in neutrophil anti-C. albicans function.
- Subjects
CANDIDA albicans; NICOTINAMIDE adenine dinucleotide phosphate; ECHINOCANDINS; ARGININE deiminase; LEUCOCYTE elastase; DEOXYRIBOZYMES
- Publication
PLoS Pathogens, 2019, Vol 15, Issue 11, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1008096