Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors
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
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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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 5

Differential recognition of O - andN -linked mannosyl residues by TLR4 and MR.

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Differential recognition of O - and...
(A) Human MNCs were stimulated with the various C. albicans strains — the parent NGY152 strain; the och1 mutant (strain NGY357; ref. 29), defective in N-linked mannosylation; and the mnt1 mnt2 mutant (strain NGY337; ref. 27), defective in O-linked mannosylation — in the presence of monoclonal antibodies against TLR4 or MR or a isotype-matched control antibody. After 24 hours’ stimulation at 37°C, supernatants were collected, and TNF concentration was measured by RIA. Results are pooled triplicate data from 2 separate experiments with a total of 8 volunteers per group. (B) Murine peritoneal macrophages from TLR4+/+ C57BL/10J and TLR4–/– ScCr mice were stimulated with the various C. albicans strains: NGY152, the och1 mutant (NGY357; ref. 29), and the mnt1 mnt2 mutant (NGY337; ref. 27). After 24 hours’ stimulation at 37°C, supernatants were collected, and TNF levels were determined by RIA. Results (mean ± SD) are pooled data from 2 separate experiments with a total of 10 mice per group. *P < 0.05 versus stimulation in the presence of control antibodies (A) or versus TLR4+/+ mice (B).