Candida albicans is a human commensal fungus known to cause mucosal infections and life-threatening invasive infections in immunocompromised patients. Macrophages are an important first line of defence against C. albicans infection, orchestrating pro-inflammatory responses through cytokine release and potentially containment of fungal pathogens through phagolysosomal degradation. However, Candida can counter-attack when challenged by macrophages. This occurs primarily by two mechanisms. Intracellularly, C. albicans switches from yeast to hyphal growth and escapes phagolysosomal containment, eventually triggering NLRP3 inflammasome-dependent pyroptosis. Pyroptotic cell death is lytic and results in fungal release. Once extracellular, progressing C. albicans infection changes the infection niche, such that rapid fungal replication results in a glucose – poor environment. This proves fatal for infected macrophages, which turn on Warburg metabolism upon microbial infection and become heavily dependent on glucose. These previous studies from our lab suggest that approaches targeting the inflammasome and immunometabolic processes could change the outcome of Candida-macrophage interactions, and ultimately impact on host survival of fungal infection.
A limitation of our current understanding of macrophage-C. albicans interactions is that it is based primarily on work with murine macrophages. In this project, we use live cell imaging to characterise the responses of human macrophages to C. albicans challenge, and investigate the mechanisms of macrophage death and inflammatory responses. Genetic or pharmacological inhibition of host and pathogen processes is used to delineate the contributions of the inflammasome pathway on the one hand, and morphogenetic switching of the pathogen and metabolic competition on the other. Human macrophages efficiently phagocytose C. albicans, but die following infection. Our initial data indicates that both pathogen morphogenetic switching and metabolic competition for glucose play a role in dictating the outcome of human macrophage-C. albicans interactions. Current work is focused on delineating the roles of the inflammasome pathway and understanding how immunometabolic competition controls inflammatory responses.