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

doi:10.1016/j.celrep.2023.113240

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

Cell Rep. 2023 Oct 31;42(10):113240. doi: 10.1016/j.celrep.2023.113240. Epub 2023 Oct 17.

Authors

Yifan Wu¹, Shuqi Du², Lynn H Bimler³, Kelsey E Mauk³, Léa Lortal⁴, Nessim Kichik⁴, James S Griffiths⁴, Radim Osicka⁵, Lizhen Song³, Katherine Polsky³, Lydia Kasper⁶, Peter Sebo⁵, Jill Weatherhead⁷, J Morgan Knight⁸, Farrah Kheradmand⁹, Hui Zheng¹⁰, Jonathan P Richardson⁴, Bernhard Hube¹¹, Julian R Naglik¹², David B Corry¹³

Affiliations

¹ 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.
² Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
³ Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁴ Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 1UL, UK.
⁵ Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic.
⁶ Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), 07737 Jena, Germany.
⁷ 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.
⁸ Departments of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁹ 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.
¹⁰ 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.
¹¹ 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. Electronic address: bernhard.hube@hki-jena.de.
¹² Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 1UL, UK. Electronic address: julian.naglik@kcl.ac.uk.
¹³ 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. Electronic address: dcorry@bcm.edu.

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.

Keywords: Alzheimer’s disease; CD11b; CP: Immunology; CP: Neuroscience; Candida albicans; Toll-like Receptor 4; amyloid beta; blood-brain barrier; candidalysin; cerebral mycosis; microglia; secreted aspartic proteinase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease / metabolism
Alzheimer Disease / microbiology
Amyloid beta-Peptides / metabolism
Animals
CD11b Antigen* / metabolism
Candida albicans / metabolism
Fungal Proteins / metabolism
Mice
Microglia* / metabolism
Microglia* / microbiology
Mycoses* / genetics
Mycoses* / metabolism
Toll-Like Receptor 4* / metabolism

Substances

Amyloid beta-Peptides
Fungal Proteins
Toll-Like Receptor 4
CD11b Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding