Toll-like receptor 4 and CD11b expressed on microglia coordinate eradication of Candida albicans cerebral mycosis

The fungal pathogen Candida albicans is linked to chronic brain diseases such as Alzheimer's disease (AD), but the molecular basis of brain anti-Candida immunity remains unknown. We show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted as-partic proteinases (Saps) and candidalysin. Saps disrupt tight junction proteins of the blood-brain barrier (BBB) to permit fungal brain invasion. Saps also hydrolyze amyloid precursor protein (APP) into amyloid D (AD)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia. Recognition of AD-like peptides and candidalysin pro-motes fungal clearance from the brain, and disruption of candidalysin recognition through CD11b markedly prolongs C. albicans cerebral mycosis. Thus, C. albicans is cleared from the brain through innate immune mechanisms involving Saps, AD, candidalysin, and CD11b.

Automated summary

The fungal pathogen Candida albicans can enter the mouse brain from the blood and trigger two neuroimmune sensing mechanisms involving secreted as-partic proteinases (Saps) and candidalysin. The Saps disrupt the blood-brain barrier and promote fungal invasion, while candidalysin engages with microglia to defend against the fungus. These findings suggest that clearance of Candida albicans from the brain is achieved through innate immune mechanisms involving Saps, AD, candidalysin, and CD11b.