Emergence, function, and therapeutic strategies to target the PD-1/PD-L1 immune checkpoint during pathogenic fungal infections

Human pathogenic fungi are ubiquitous in the environment and induce an expanding repertoire of devastating diseases globally. Upon fungal invasion, the fungus adopts multiple strategies to adapt to, or eliminate, hostile environmental conditions, which immune checkpoints serve as one of the mechanism for fungal evasion. Programmed death receptor-1 (PD-1), an immunosuppressive molecule, transmits inhibitory signals upon binding to its ligand PD-L1. During infection, aberrant activation of the PD-1/PD-L1 pathway has been proven to facilitate immune evasion by the pathogen. In this review, we summarize the roles of PD-1/PD-L1 in fungal infection. First, the molecular structures and function of PD-1 and PD-L1 are described. Then, we highlight the dynamic expression patterns and regulatory mechanisms of PD-1/PD-L1 during fungal invasion. Potential therapeutics based on PD-1/PD-L1-blocking to enhance antifungal immunity and improve clinical outcomes are also discussed. These insights reveal future directions regarding PD-1/PD-L1 and immune checkpoint-based therapies for preventing pathogenic fungi infections.