title: Differential virulence of Candida glabrata glycosylation mutants.
abstract: The fungus Candida glabrata is an important and increasingly common pathogen of humans, particularly in immunocompromised hosts. Despite this, little is known about the attributes that allow this organism to cause disease or its interaction with the host immune system. However, in common with other fungi, the cell wall of C. glabrata is the initial point of contact between the host and pathogen, and as such, it is likely to play an important role in mediating interactions and hence virulence. Here, we show both through genetic complementation and polysaccharide structural analyses that C. glabrata ANP1, MNN2, and MNN11 encode functional orthologues of the respective Saccharomyces cerevisiae mannosyltransferases. Furthermore, we show that deletion of the C. glabrata Anp1, Mnn2, and Mnn11 mannosyltransferases directly affects the structure of the fungal N-linked mannan, in line with their predicted functions, and this has implications for cell wall integrity and consequently virulence. C. glabrata anp1 and mnn2 mutants showed increased virulence, compared with wild-type (and mnn11) cells. This is in contrast to Candida albicans where inactivation of genes involved in mannan biosynthesis has usually been linked to an attenuation of virulence. In the long term, a better understanding of the attributes that allow C. glabrata to cause disease will provide insights that can be adopted for the development of novel therapeutic and diagnostic approaches.
authors.affiliation: Department of Microbiology, Imperial College London, London, SW7 2AZ, United Kingdom.
authors.forename: Lara
authors.initials: L
authors.lastname: West
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Lowman
authors.forename: Héctor M
authors.initials: HM
authors.lastname: Mora-Montes
authors.forename: Sarah
authors.initials: S
authors.lastname: Grubb
authors.forename: Craig
authors.initials: C
authors.lastname: Murdoch
authors.forename: Martin H
authors.initials: MH
authors.lastname: Thornhill
authors.forename: Neil A R
authors.initials: NA
authors.lastname: Gow
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.forename: Ken
authors.initials: K
authors.lastname: Haynes
mesh_terms: D000818:Animals; D041221:Candida glabrata / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity; D002177:Candidiasis / Q000382:microbiology; D002240:Carbohydrate Sequence; D002460:Cell Line; D002473:Cell Wall / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000382:microbiology; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D005816:Genetic Complementation Test; D006031:Glycosylation; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008351:Mannans / Q000737:chemistry / Q000378:metabolism; D008364:Mannosyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics
chemical_list: D005656:Fungal Proteins; D007527:Isoenzymes; D008351:Mannans; D029701:Saccharomyces cerevisiae Proteins; C584103:Anp1 protein, Candida glabata; D008364:Mannosyltransferases; C584104:Mnn11 protein, Candida glabata; C584105:Mnn2 protein, Candida glabata
keywords: Candida albicans; Cell Wall; Fungi; Host-Pathogen Interactions; Virulence Factors