Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors.
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 beta-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 beta-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.
Netea
Mihai G
MG
Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.netea@aig.umcn.nl
Gow
Neil A R
NA
Munro
Carol A
CA
Bates
Steven
S
Collins
Claire
C
Ferwerda
Gerben
G
Hobson
Richard P
RP
Bertram
Gwyneth
G
Hughes
H Bleddyn
HB
Jansen
Trees
T
Jacobs
Liesbeth
L
Buurman
Ed T
ET
Gijzen
Karlijn
K
Williams
David L
DL
Torensma
Ruurd
R
McKinnon
Alistair
A
MacCallum
Donna M
DM
Odds
Frank C
FC
Van der Meer
Jos W M
JW
Brown
Alistair J P
AJ
Kullberg
Bart Jan
BJ
D000818:Animals; D002176:Candida albicans / Q000235:genetics / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002473:Cell Wall / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D016207:Cytokines / Q000276:immunology; D005936:Glucans / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008351:Mannans / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011975:Receptors, Mitogen / Q000737:chemistry / Q000276:immunology*; D051193:Toll-Like Receptors / Q000737:chemistry / Q000276:immunology*
D016207:Cytokines; D005936:Glucans; D008351:Mannans; D011975:Receptors, Mitogen; D051193:Toll-Like Receptors