Inborn Errors of Immunity Dissect Critical Pathways in Human Antifungal Defense

The human immune system constantly adapts to emerging infectious threats, yet its mechanisms against fungal pathogens are complex and often poorly understood. Inborn Errors of Immunity (IEIs), caused by single-gene defects, offer a unique lens to pinpoint specific vulnerabilities and essential components of antifungal defense. Current standard-of-care for severe fungal infections often relies on broad-spectrum antifungals, which can have significant side effects and may not address underlying host immune deficiencies. This review addresses the critical gap in understanding the precise genetic and immunological pathways that govern susceptibility to fungal infections, aiming to translate this knowledge into more targeted diagnostics and therapies.

This review synthesizes current understanding of fungal immunity by examining Inborn Errors of Immunity (IEIs). It integrates recent advances across several key immunological domains, including innate fungal recognition, the effector mechanisms of neutrophils and mononuclear phagocytes, and critical signaling pathways. The authors specifically focused on the roles of CARD9/NF-κB signaling, the IL-17/IL-23 and IL-12/IFN-gamma cytokine axes, and various transcription-factor defects. The review correlates these genetic and mechanistic insights with susceptibility to a range of pathogenic fungi, including Candida, Aspergillus, Pneumocystis, Cryptococcus, and dimorphic fungi, as well as other moulds. It also discusses acquired phenocopies mediated by anti-cytokine autoantibodies.

The review highlights how genetically defined Inborn Errors of Immunity (IEIs) provide a unique framework for dissecting the intricate host-pathogen interactions critical for antifungal defense. It elucidates how single-gene defects reveal essential pathways in immunity, from initial fungal recognition to downstream effector functions. Specific emphasis is placed on the pivotal roles of CARD9/NF-κB signaling in mediating inflammatory responses and immune cell activation, and the distinct contributions of the IL-17/IL-23 and IL-12/IFN-gamma cytokine axes in orchestrating adaptive antifungal immunity. Furthermore, the review details how various transcription-factor defects can profoundly shape susceptibility to specific fungal pathogens. It also integrates the concept of acquired phenocopies, where anti-cytokine autoantibodies mimic genetic defects, leading to similar clinical vulnerabilities. This comprehensive synthesis translates complex immunological mechanisms into practical clinical red flags and diagnostic algorithms. > The review underscores that genetically defined IEIs are invaluable tools for studying not only fungal infections but also complex fungal-bacterial, fungal-mycobacterial, and fungal-viral co-infections, revealing the hierarchy and plasticity of host defense.