Disrupting the Dok3–Card9 interaction with synthetic peptides enhances antifungal effector functions of human neutrophils

• Main Authors: Loh, Jia Tong, Teo, Joey Kay Hui, Kannan, Srinivasaraghavan, Verma, Chandra Shekhar, Lim, Hong-Hwa, Lam, Kong-Peng
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Biological sciences; Neutrophils; Antifungal Immunity
• Online Access: https://hdl.handle.net/10356/171781
• Institution: Nanyang Technological University

Invasive fungal disease is an emerging and serious public health threat globally. The expanding population of susceptible individuals, together with the rapid emergence of multidrug-resistant fungi pathogens, call for the development of novel therapeutic strategies beyond the limited repertoire of licensed antifungal drugs. Card9 is a critical signaling molecule involved in antifungal defense; we have previously identified Dok3 to be a key negative regulator of Card9 activity in neutrophils. In this study, we identified two synthetic peptides derived from the coiled-coil domain of Card9, which can specifically block Dok3-Card9 binding. We showed that these peptides are cell-permeable, non-toxic, and can enhance antifungal cytokine production and the phagocytosis of human neutrophils upon fungal infection. Collectively, these data provide a proof of concept that disrupting the Dok3-Card9 interaction can boost the antifungal effector functions of neutrophils; they further suggest the potential utility of these peptide inhibitors as an immune-based therapeutic to fight fungal infection.