Mechanisms of <i>Talaromyces marneffei</i> induced CNS injury: Synergistic roles of tauopathy, pyroptosis, and microglial inflammation

<i>Talaromyces marneffei</i> (<i>T. marneffei</i>) is an opportunistic, dimorphic fungus that has been clinically reported to involve the central nervous system (CNS). However, its neuroinvasive capacity and the underlying pathogenic mechanisms remain poorly understood. In this study, <i>T. marneffei</i> infection was found to impair learning, memory, and motor balance in mice, as demonstrated by Morris water maze and accelerating rotarod assays. Viable <i>T. marneffei</i> was subsequently isolated from hippocampus and cortex through fungal cultures, confirming its ability to invade the CNS. Histopathological analysis revealed CNS damage following infection, characterized by neuronal pyknosis, neurofibrillary tangles, and an increased presence of glial cells in the cortex. To investigate the underlying mechanisms, transcriptomic profiling showed significant enrichment of neurodegeneration pathways, with elevated Tau and GSDMD expression in hippocampal and cortical regions as well as N2a cells. Additionally, neuronal damage was exacerbated by indirect neurotoxicity mediated by microglial M1 polarization, accompanied by increased levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). In conclusion, our findings uncover for the first time a dual-pathogenic mechanism by which <i>T. marneffei</i> induces CNS injury: direct neuronal damage via Tau pathology and GSDMD-dependent pyroptosis and indirect inflammation-mediated injury via M1-polarized microglia. These insights not only advance our understanding of fungal neuroinvasion but also provide a foundation for the development of targeted therapies.