Physiological Role of Dok3 in Candidiasis

Invasive fungal infection is a serious health threat with high morbidity and mortality, and Candida species are the most prevalent causative agents of such infection. However, current antifungal drugs only demonstrate partial success in improving prognosis. Together with the rapid emergence of drug resistance among Candida species, there is a pressing need to develop novel antifungal therapies to improve clinical outcomes. Understanding the mechanistic interaction between host immune system and fungal pathogens holds the key for uncovering novel immune-based treatments to combat candidaemia. Our preliminary study suggests that Dok3, an adaptor protein involved in immune receptor signaling, acts as a negative regulator of antifungal immunity in neutrophils. As such, we aim to elucidate the underlying mechanisms of Dok3 in antifungal immune response by determining their role in the regulation of neutrophilic antifungal effector functions, which include phagocytosis, secretion of pro-inflammatory cytokines, production of reactive oxygen species, release of neutrophil extracellular traps, and the formation of neutrophil granules. In addition, the signaling pathway of Dok3 during antifungal immune response will be examined through microarray, mass spectrometry and biochemical approaches. By dissecting the mechanistic role of Dok3 in antifungal immunity, we will be able to propose the potential utility of Dok3 inhibitors as novel therapies and prophylaxis for invasive candidiasis. Such immune-based approach could act as an adjunctive therapy to current antifungal drugs for further improvement of outcomes in fungal-infected patients. As such, our proposed research will not only extend our understanding about the mechanisms regulating host antifungal immune response, but may also have translationally relevant implications for the development of novel antifungal drugs and infection control.