1. Toll-like receptor 4 and CD11b expressed on microglia coordinate eradication of Candida albicanscerebral mycosis
- Author
-
Wu, Yifan, Du, Shuqi, Bimler, Lynn H., Mauk, Kelsey E., Lortal, Léa, Kichik, Nessim, Griffiths, James S., Osicka, Radim, Song, Lizhen, Polsky, Katherine, Kasper, Lydia, Sebo, Peter, Weatherhead, Jill, Knight, J. Morgan, Kheradmand, Farrah, Zheng, Hui, Richardson, Jonathan P., Hube, Bernhard, Naglik, Julian R., and Corry, David B.
- Abstract
The fungal pathogen Candida albicansis linked to chronic brain diseases such as Alzheimer’s disease (AD), but the molecular basis of brain anti-Candidaimmunity remains unknown. We show that C. albicansenters 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 vitrowhile 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. albicanscerebral mycosis. Thus, C. albicansis cleared from the brain through innate immune mechanisms involving Saps, Aβ, candidalysin, and CD11b.
- Published
- 2023
- Full Text
- View/download PDF