Cryptococcal Infection Across Disease Stages: Host-Pathogen Interactions, Tissue Niches, and Translational Priorities.

Cryptococcosis often begins in the lungs and may later reach the central nervous system, where it can lead to severe or fatal disease. The course of infection is shaped by changing interactions between host cells, fungal adaptive states, and local tissue environments. Many virulence factors and immune responses have been studied in detail, but the evidence remains divided across organs, cell types, and experimental systems. As a result, pulmonary infection is better understood than later stages, including dissemination, crossing of the blood-brain barrier, CNS involvement, and long-term persistence. In this review, we use a stage-resolved phenomic framework to connect host cell states, fungal adaptive phenotypes, and tissue niches throughout the course of infection. Evidence from multi-omics studies, spatial analyses, cellular experiments, animal models, and clinical cohorts is brought together to show how phenotypic features differ between stages and how uneven the current evidence base remains. The strongest evidence remains concentrated in pulmonary infection, whereas dissemination, crossing of the blood-brain barrier, and CNS disease are supported by more model-dependent data. Evidence for persistence and reactivation is the most limited. By organizing these findings into a disease-course map, this review outlines testable questions for biomarker discovery, host-directed therapy, and risk stratification in cryptococcal infection.