Abstract
Invasive fungal infection is a serious health threat with high morbidity and mortality. Current antifungal drugs only demonstrate partial success in improving prognosis. Furthermore, mechanisms regulating host defense against fungal pathogens remain elusive. Here, we report that the downstream of kinase 3 (Dok3) adaptor negatively regulates antifungal immunity in neutrophils. Our data revealed that Dok3 deficiency increased phagocytosis, proinflammatory cytokine production, and netosis in neutrophils, thereby enhancing mutant mouse survival against systemic infection with a lethal dose of the pathogenic fungus Candida albicans. Biochemically, Dok3 recruited protein phosphatase 1 (PP1) to dephosphorylate Card9, an essential player in innate antifungal defense, to dampen downstream NF-κB and JNK activation and immune responses. Thus, Dok3 suppresses Card9 signaling, and disrupting Dok3-Card9 interaction or inhibiting PP1 activity represents therapeutic opportunities to develop drugs to combat candidaemia.
Highlights
Invasive Candida infection is a major public health concern due to its high mortality rates and increased costs of treatment [1]
We further investigated the fungicidal activity of neutrophils by infecting the cells with unopsonized C. albicans at a higher MOI, and downstream of kinase 3 (Dok3)–/– neutrophils were able to significantly inhibit the germination of unopsonized C. albicans as compared with Dok3+/+ neutrophils (Figure 2B)
To further address whether Dok3 deficiency contributes to the ability of neutrophils to counter large and invasive fungal hyphae structures that cannot be phagocytosed [33], we examined the release of neutrophil extracellular traps (NETs) following their stimulation with heat-killed C. albicans (HKCA) in preformed hyphae
Summary
Invasive Candida infection is a major public health concern due to its high mortality rates and increased costs of treatment [1]. The incidence of candidiasis rises with the advancement of medicine, mainly because of the emergence of large numbers of invasive procedures and the extensive use of broad-spectrum antibiotics [2]. Current antifungal drugs only demonstrate partial success in improving prognosis, and the rapid emergence of drug resistance among Candida species is a growing problem [4]. There is a pressing need to develop novel antifungal therapies to improve clinical outcomes. Understanding the mechanistic interaction between host immune cells and fungal pathogens holds the key for uncovering novel immune-based treatments to combat candidiasis [5]
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