Candida albicans triggers NADPH oxidase-independent 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+-PKC?-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.

SUBMITTER: Wu SY 

PROVIDER: S-EPMC6834254 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature