Fungi increasingly threaten health globally. Mycoses range from life-threatening, often iatrogenic conditions, to enigmatic syndromes occurring without apparent immunosuppression. Despite some recent advances in antifungal drug development, complementary therapeutic strategies are essential for addressing these opportunistic pathogens. One promising avenue is leveraging host immunity to combat fungal infections; this necessitates deeper understanding of the molecular immunology of human fungal susceptibility to differentiate beneficial versus harmful immunopathological responses. Investigating human models of fungal diseases in natural settings, particularly through genetic immunodeficiencies and ethnographic-specific genetic vulnerabilities, reveals crucial immune pathways essential for fighting various yeasts and molds. This review highlights the diversity in intrinsic fungal susceptibility across individuals and populations, through genetic- and autoantibody-mediated processes, complementing previous principles learned from animal studies and iatrogenic contexts. Improved understanding of human immunity to fungal diseases will facilitate the development of host-directed immunotherapies and targeted public health interventions, paving the way for precision medicine in fungal disease management.
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