HOST CELL RESPONSES IN THE BRAIN DURING CRYPTOCOCCAL MENINGOENCEPHALITIS

Abstract

Cryptococcus, a neurotropic fungus identified as a critical-priority pathogen by the World Health Organization (WHO), causes cryptococcal meningoencephalitis (CM), responsible for nearly 200,000 deaths annually, making it the second leading cause of death in HIV/AIDS patients. Although this is a threat to public health, neither effective diagnostics nor treatments are available, and existing treatments are not standardized, leading to poor prognosis and high mortality. Despite its clinical importance, host brain responses during CM remain poorly understood. Yet, host responses in the brain during CM remain severely underexplored. Employing a non-acute systemic mouse model of CM, we observed fungal infiltration into the brain within three days, but full microglia reactivity took 14 days. Microglia, though expected to act as sentinels, are slow to respond, partly due to their inability to detect fungal yeast and reliance on IFNγ production by T cells. Once activated, microglia upregulate Spp1, encoding osteopontin (OPN) and known to be highly expressed in neurodegenerative conditions. Our findings demonstrate that microglia-derived OPN negatively impacts the host by altering peripheral immune responses during disseminated Cryptococcus infection. Consequently, Cryptococcus exploits the delayed host response to establish brain infection, with activated microglia producing OPN that is detrimental to the host’s health.