Toll-like receptor 4 and CD11b expressed on microglia coordinate eradication of Candida albicans cerebral mycosis
Yifan Wu,
Shuqi Du,
Lynn H. Bimler,
Kelsey E. Mauk,
Léa Lortal,
Nessim Kichik,
James S. Griffiths,
Radim Osicka,
Lizhen Song,
Katherine Polsky,
Lydia Kasper,
Peter Sebo,
Jill Weatherhead,
J. Morgan Knight,
Farrah Kheradmand,
Hui Zheng,
Jonathan P. Richardson,
Bernhard Hube,
Julian R. Naglik,
David B. Corry
Affiliations
Yifan Wu
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
Shuqi Du
Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Lynn H. Bimler
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Kelsey E. Mauk
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Léa Lortal
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 1UL, UK
Nessim Kichik
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 1UL, UK
James S. Griffiths
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 1UL, UK
Radim Osicka
Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
Lizhen Song
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Katherine Polsky
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Lydia Kasper
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), 07737 Jena, Germany
Peter Sebo
Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
Jill Weatherhead
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
J. Morgan Knight
Departments of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Farrah Kheradmand
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Departments of Pathology & 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
Hui Zheng
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
Jonathan P. Richardson
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 1UL, UK
Bernhard Hube
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), 07737 Jena, Germany; Institute of Microbiology, Friedrich Schiller University, 07737 Jena, Germany; Corresponding author
Julian R. Naglik
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 1UL, UK; Corresponding author
David B. Corry
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Departments of Pathology & 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; Corresponding author
Summary: 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.
