The Mechanism of Candida albicans-Induced Neutrophil Extracellular Traps Formation

Candida albicans is a dimorphic fungus. It is a commensal in healthy individuals and becomes an opportunistic pathogen in immunocompromised hosts causing mucosal or systemic candidiasis. Previous studies show that, CGD and neutropenia patients are susceptible to systemic candidiasis showing that neutrophil is important to host defense against C. albicans. Neutrophils kill pathogens by neutrophil extracellular traps (NETs), a web like structure composed of chromatins, granular- and cytosolic proteins. Previous studies showed that C. albicans induce NETs via ROS-dependent as well as -independent mechanisms and NETs kill C. albicans. Here, I investigated the mechanism of NETs formation in response to stimulation by opsonized and unopsonized C. albicans. Neutrophils stimulated with both opsonized and unopsonized C. albicans released NETs. Comparing NETs formation of neutrophils from wild type and Ncf-1 knockout mice in response to opsonized and unopsonized C. albicans, we found that opsonized C. albicans induced-NETs formation was via NADPH oxidase-dependent mechanism but unopsonized C. albicans induced NETs did not require NADPH oxidase mediated-ROS production. Comparing neutrophils from CR3 KO and WT mice, I discovered that neutrophils recognized opsonized C. albicans via CR3. CR3 engagement activated PKC, PI3K, and Syk signaling pathway(s) resulting in NADPH oxidase-dependent NETs production. On the other hand, unopsonized C. albicans is recognized by Dectin-2 and activated Syk, PKCδ, P38 and ERK signaling pathway(s). In conclusion opsonized and unopsonized C. albicans are recognized by different receptor and induce NETs production via different pathways.