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The Mnn2 mannosyltransferase family modulates mannoprotein fibril length, immune recognition and virulence of Candida albicans.
- Source :
-
PLoS pathogens [PLoS Pathog] 2013; Vol. 9 (4), pp. e1003276. Date of Electronic Publication: 2013 Apr 25. - Publication Year :
- 2013
-
Abstract
- The fungal cell wall is the first point of interaction between an invading fungal pathogen and the host immune system. The outer layer of the cell wall is comprised of GPI anchored proteins, which are post-translationally modified by both N- and O-linked glycans. These glycans are important pathogen associated molecular patterns (PAMPs) recognised by the innate immune system. Glycan synthesis is mediated by a series of glycosyl transferases, located in the endoplasmic reticulum and Golgi apparatus. Mnn2 is responsible for the addition of the initial α1,2-mannose residue onto the α1,6-mannose backbone, forming the N-mannan outer chain branches. In Candida albicans, the MNN2 gene family is comprised of six members (MNN2, MNN21, MNN22, MNN23, MNN24 and MNN26). Using a series of single, double, triple, quintuple and sextuple mutants, we show, for the first time, that addition of α1,2-mannose is required for stabilisation of the α1,6-mannose backbone and hence regulates mannan fibril length. Sequential deletion of members of the MNN2 gene family resulted in the synthesis of lower molecular weight, less complex and more uniform N-glycans, with the sextuple mutant displaying only un-substituted α1,6-mannose. TEM images confirmed that the sextuple mutant was completely devoid of the outer mannan fibril layer, while deletion of two MNN2 orthologues resulted in short mannan fibrils. These changes in cell wall architecture correlated with decreased proinflammatory cytokine induction from monocytes and a decrease in fungal virulence in two animal models. Therefore, α1,2-mannose of N-mannan is important for both immune recognition and virulence of C. albicans.
- Subjects :
- Animals
Candida albicans enzymology
Candidiasis immunology
Cell Wall chemistry
Cell Wall immunology
Female
Fungal Proteins genetics
Fungal Proteins immunology
Fungal Proteins metabolism
Humans
Mannans chemistry
Mannose chemistry
Mannosyltransferases genetics
Membrane Glycoproteins metabolism
Mice
Mice, Inbred BALB C
Polysaccharides metabolism
Receptors, Pattern Recognition immunology
Receptors, Pattern Recognition metabolism
Sequence Alignment
Sequence Deletion
Candida albicans immunology
Candida albicans pathogenicity
Mannans immunology
Mannose metabolism
Mannosyltransferases metabolism
Membrane Glycoproteins immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 9
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 23633946
- Full Text :
- https://doi.org/10.1371/journal.ppat.1003276