According to the Global Action Fund for Fungal Infections, more than 300 million people around the world suffer from serious fungal infections. While several antifungal drugs are available in clinics and hospitals, their efficacy is declining due to the advent of drug-resistant fungal strains.
“Drug resistance among pathogenic fungi is surfacing at an accelerated rate. An example is the emergence of the superbug Candida auris that, in recent times, has caused infections in hospitals worldwide,” warned Kong-Peng Lam, Executive Director at A*STAR’s Bioprocessing Technology Institute (BTI). Because of the urgent need for new ideas and ways to combat fungal infection, Lam and his team began exploring how the body naturally protects itself against disease-causing fungi.
The researchers focused their attention specifically on neutrophils, an abundant type of white blood cell that forms the first line of defense in antifungal immunity. The team discovered that the loss of a protein called Dok3 within neutrophils boosted the neutrophils’ antifungal capabilities.
“Using a technique called co-immunoprecipitation, which shows binding between different proteins, we identified that Dok3 bridges the interaction between two other proteins—PP1 and Card9,” said Jia-Tong Loh, a Research Fellow in Lam’s lab and the lead author of the study. When close together, PP1 inhibits the function of Card9, resulting in the suppression of neutrophil responses to fungal infection. Therefore, when Dok3 is deleted, the antifungal activity of neutrophils is restored.
Lam’s team further showed that the genetic deletion of Dok3 enhanced survival rates in mice with systemic Candida infections. This was attributed to a stronger neutrophil presence in the brains and kidneys of Dok3-deleted mice compared to normal mice used as a control group, which resulted in better control of infection in Dok3-deleted mice.
“Now that we know Dok3 suppresses antifungal defenses, we can potentially remove the brakes on antifungal immunity. Implementing an immune-based approach can reduce fungicide use in the clinics, slow down the evolution of fungi resistance and improve the clinical outcomes of fungal-infected patients,” said Lam, who recommended a two-pronged approach—antifungal drugs to kill the pathogen, coupled with drug compounds that target Dok3 to enhance immune-mediated clearance of infection.
In collaboration with scientists from the Institute of Molecular and Cell Biology (IMCB), Lam's team plans to screen for potential drugs that disrupt Dok3-Card9 binding. If successful, this discovery may lead to a novel immune-based therapy for life-threatening fungal infections.
The A*STAR-affiliated researchers contributing to this research are from the Bioprocessing Technology Institute (BTI) and the Institute of Molecular and Cell Biology (IMCB).
