Molecular Interplay in CNS Fungal Invasion: Strategies for Invasion, Immune Evasion, and Host Countermeasures

Fungal infections of the central nervous system (CNS) represent severe clinical threats with high mortality, stemming from intricate molecular interplay between neurotropic fungi and specialized host defenses. This review dissects the mechanisms underpinning fungal CNS invasion—including enzymatic blood-brain barrier (BBB) disruption, transcellular transport, and "Trojan horse" evasion within phagocytes—alongside evolved immune escape tactics such as molecular camouflage by capsular polysaccharides, biofilm-mediated resistance, and immunosuppressive microenvironment shaping. Critically, CNS-resident immune cells, including microglia, utilize surface C-type lectin receptors (CLRs) and Toll-like receptors (TLRs) to initiate antifungal immunity through Syk/CARD9-dependent signaling and inflammasome activation. However, fungi subvert these defenses by neutralizing phagosomal acidity, inducing non-lytic expulsion, and hijacking metabolic pathways to enhance virulence and drug tolerance. The dynamic coevolutionary arms race manifests in chronic CNS colonization via Th2 polarization, contrasting with the dual-edged role of adaptive immunity where CD4⁺ T cell responses aid pathogen clearance yet exacerbate neuroinflammation. Overcoming therapeutic challenges, particularly limited antifungal BBB penetration and rising drug resistance, requires deciphering these host-pathogen molecular dialogues to design targeted interventions disrupting immune evasion or bolstering CNS-specific immunity.