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

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

Centre for Host Microbiome Interactions

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

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.

Original language	English
Number of pages	113240
Journal	Cell Reports
Volume	42
Issue number	10
Early online date	18 Oct 2023
DOIs	https://doi.org/10.1016/j.celrep.2023.113240
Publication status	Published - Oct 2023

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Wu, Y., Du, S., Bimler, L. H., Mauk, K. E., Lortal, L., Kichik, N., Griffiths, J. S., Osicka, R., Song, L., Polsky, K., Kasper, L., Sebo, P., Weatherhead, J., Knight, J. M., Kheradmand, F., Zheng, H., Richardson, J. P., Hube, B., Naglik, J. R., & Corry, D. B. (2023). Toll-like receptor 4 and CD11b expressed on microglia coordinate eradication of Candida albicans cerebral mycosis. Cell Reports, 42(10). https://doi.org/10.1016/j.celrep.2023.113240

@article{959c5a57d1c84705a9585701d8efdd84,

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

abstract = "The fungal pathogen Candida albicans is linked to chronic brain diseases such as Alzheimer{\textquoteright}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.",

author = "Yifan Wu and Shuqi Du and Bimler, {Lynn h.} and Mauk, {Kelsey e.} and L{\'e}a Lortal and Nessim Kichik and Griffiths, {James s.} and Radim Osicka and Lizhen Song and Katherine Polsky and Lydia Kasper and Peter Sebo and Jill Weatherhead and Knight, {J. morgan} and Farrah Kheradmand and Hui Zheng and Richardson, {Jonathan p.} and Bernhard Hube and Naglik, {Julian r.} and Corry, {David b.}",

year = "2023",

month = oct,

doi = "10.1016/j.celrep.2023.113240",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier BV",

number = "10",

}

Wu, Y, Du, S, Bimler, LH, Mauk, KE, Lortal, L, Kichik, N, Griffiths, JS, Osicka, R, Song, L, Polsky, K, Kasper, L, Sebo, P, Weatherhead, J, Knight, JM, Kheradmand, F, Zheng, H, Richardson, JP, Hube, B, Naglik, JR & Corry, DB 2023, 'Toll-like receptor 4 and CD11b expressed on microglia coordinate eradication of Candida albicans cerebral mycosis', Cell Reports, vol. 42, no. 10. https://doi.org/10.1016/j.celrep.2023.113240

TY - JOUR

T1 - Toll-like receptor 4 and CD11b expressed on microglia coordinate eradication of Candida albicans cerebral mycosis

AU - Wu, Yifan

AU - Du, Shuqi

AU - Bimler, Lynn h.

AU - Mauk, Kelsey e.

AU - Lortal, Léa

AU - Kichik, Nessim

AU - Griffiths, James s.

AU - Osicka, Radim

AU - Song, Lizhen

AU - Polsky, Katherine

AU - Kasper, Lydia

AU - Sebo, Peter

AU - Weatherhead, Jill

AU - Knight, J. morgan

AU - Kheradmand, Farrah

AU - Zheng, Hui

AU - Richardson, Jonathan p.

AU - Hube, Bernhard

AU - Naglik, Julian r.

AU - Corry, David b.

PY - 2023/10

Y1 - 2023/10

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2023.113240

DO - 10.1016/j.celrep.2023.113240

M3 - Article

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 10

ER -

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

Abstract

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