Toll-Like Receptor 4 and CD11b Expressed on Microglia Coordinate Eradication of Candida albicans Cerebral Mycosis

Authors

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

Publication Date

10-31-2023

Journal

Cell Reports

DOI

10.1016/j.celrep.2023.113240

PMID

37819761

PMCID

PMC10753853

PubMedCentral® Posted Date

12-28-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Mice, Alzheimer Disease, Amyloid beta-Peptides, Candida albicans, Fungal Proteins, Microglia, Mycoses, Toll-Like Receptor 4, CD11b Antigen

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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