Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors
Mihai G. Netea, … , Alistair J.P. Brown, Bart Jan Kullberg
Mihai G. Netea, … , Alistair J.P. Brown, Bart Jan Kullberg
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1642-1650. https://doi.org/10.1172/JCI27114.
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Research Article Microbiology

Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors

Abstract

The fungal pathogen Candida albicans has a multilayered cell wall composed of an outer layer of proteins glycosylated with N- or O-linked mannosyl residues and an inner skeletal layer of β-glucans and chitin. We demonstrate that cytokine production by human mononuclear cells or murine macrophages was markedly reduced when stimulated by C. albicans mutants defective in mannosylation. Recognition of mannosyl residues was mediated by mannose receptor binding to N-linked mannosyl residues and by TLR4 binding to O-linked mannosyl residues. Residual cytokine production was mediated by recognition of β-glucan by the dectin-1/TLR2 receptor complex. C. albicans mutants with a cell wall defective in mannosyl residues were less virulent in experimental disseminated candidiasis and elicited reduced cytokine production in vivo. We concluded that recognition of C. albicans by monocytes/macrophages is mediated by 3 recognition systems of differing importance, each of which senses specific layers of the C. albicans cell wall.

Authors

Mihai G. Netea, Neil A.R. Gow, Carol A. Munro, Steven Bates, Claire Collins, Gerben Ferwerda, Richard P. Hobson, Gwyneth Bertram, H. Bleddyn Hughes, Trees Jansen, Liesbeth Jacobs, Ed T. Buurman, Karlijn Gijzen, David L. Williams, Ruurd Torensma, Alistair McKinnon, Donna M. MacCallum, Frank C. Odds, Jos W.M. Van der Meer, Alistair J.P. Brown, Bart Jan Kullberg

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Figure 1

Cell wall morphology in the C. albicans strains used in this study.

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Cell wall morphology in the C. albicans ...
(A–E) TEM micrographs. (A) Wild-type strain NGY152 [CAI-4 plus CIp10 vector]. (B) och1 null (strain NGY357; ref. 26) or doxycycline-regulated conditional (strain NGY361; ref. 29) mutants, which are defective in the branched outer N-linked mannosyl chains. (C) mnt1 mnt2 mutant (strain NGY337; ref. 27), which lacks 4 terminal O-linked α1,2-mannosyl residues. (D) pmr1 mutant (strain NGY355; ref. 26), which has gross defects in mannosylation, characterized by absence of phosphomannan and reduced O-linked and N-linked glycans. (E) mnn4 mutant (strain CDH15; ref. 28), which lacks phosphomannan. Scale bar: 100 nm. (F and G) Structure of the N- (F) and O-linked (G) glycans and the site of action of deleted gene products. Man, mannosyl; β-GlcNAc, β N-acetylglucosamine.