Cryptococcus exploits delayed microglial activation, and microglial osteopontin/Spp1 impairs peripheral host control.

Cryptococcus, a neurotropic fungus classified as a critical-priority pathogen by the World Health Organization (WHO), causes cryptococcal meningoencephalitis (CM), the second leading cause of death in HIV/AIDS patients. Despite its clinical importance, host brain responses during CM remain poorly understood. In a mouse systemic infection model, Cryptococcus infiltrates the brain within a day. However, full activation of microglia and recruitment of leukocytes takes 14 days, a delay not observed in brain infections caused by Candida albicans. Microglia exhibit limited ability to directly detect Cryptococcus, and their activation depends on interferon (IFN)-γ from Th1 cells. Therefore, adaptive immunity (Th1 responses) precedes innate immune responses (microglial activation) in the brain during CM. Moreover, microglia-derived osteopontin (OPN/Spp1) exacerbates CM by altering peripheral immunity and increasing fungal loads in peripheral organs. These findings reveal a uniquely slow host cellular response to Cryptococcus brain infiltration, allowing the fungus an extended window to establish the infection.