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 aspartic 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 β (Aβ)-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 Aβ-like peptides and candidalysin promotes 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, Aβ, candidalysin, and CD11b.

Centre for Host Microbiome Interactions Faculty of Dentistry Oral and Craniofacial Sciences King's College London London SE1 1UL UK

Department of Medicine Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA

Department of Medicine Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA; Department of Pediatrics Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA

Department of Medicine Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA; Department of Pediatrics Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA; National School of Tropical Medicine Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA

Department of Medicine Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA; Departments of Pathology and Immunology Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA; Biology of Inflammation Center Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA; Michael E DeBakey VA Center for Translational Research on Inflammatory Diseases Houston TX 77030 USA

Department of Microbial Pathogenicity Mechanisms Leibniz Institute for Natural Product Research and Infection Biology Hans Knoell Institute Jena 07737 Jena Germany

Department of Microbial Pathogenicity Mechanisms Leibniz Institute for Natural Product Research and Infection Biology Hans Knoell Institute Jena 07737 Jena Germany; Institute of Microbiology Friedrich Schiller University 07737 Jena Germany

Department of Neuroscience Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA

Department of Neuroscience Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA; Huffington Center on Aging Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA

Departments of Pathology and Immunology Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA

Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

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