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 4

Reintegration of the defective genes restores cytokine production.

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Reintegration of the defective genes restores cytokine production. (A) M...
(A) MNCs were stimulated with the parent NGY152 strain, the N-linked mannosyl-defective C. albicans strain (och1; strain NGY357; ref. 29), and the complemented reintegrant och1/och1/OCH1 strain (strain NGY358). (B) Stimulation was also performed with the conditional doxycycline-dependent mutant (pTET/och1; strain NGY361; ref. 29) in both the absence and the presence of doxycycline (doxy). (C) Comparison of the mnt1 mnt2 mutant (strain NGY337; ref. 27), defective in O-linked mannosyl residues, with the mnt1 mnt2 + MNT1 reintegrant strain (strain NGY335; ref. 27). After 24 hours’ stimulation at 37°C, supernatants were collected, and cytokines were determined by RIA or ELISA. Results (mean ± SD) are pooled triplicate data from 2 separate experiments with a total of 8 volunteers per group. *P < 0.05; **P < 0.01 versus wild-type.