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

Medical Sciences Amyloid beta-Peptides CD11b Antigen QH301-705.5 Medical Immunology 610 Diseases CP: Immunology Article 3. Good health Fungal Proteins Toll-Like Receptor 4 Mice Immune System Diseases Mycoses Alzheimer Disease Allergy and Immunology CP: Neuroscience 616 Candida albicans Medical Specialties Medicine and Health Sciences Animals Microglia Biology (General)
DOI: 10.1016/j.celrep.2023.113240 Publication Date: 2023-10-17T09:29:41Z
ABSTRACT
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.
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