SemOpenAlex |

SemOpenAlex

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2052675223> ?p ?o ?g. }

Showing items 1 to 100 of ±111 with 100 items per page.

W2052675223 endingPage "30526" @default.
W2052675223 startingPage "30520" @default.
W2052675223 abstract "In a series of studies, we have shown thatCandida albicans synthesizes a glycolipid, phospholipomannan (PLM), which reacted with antibodies specific for β-1,2-oligomannosides and was biosynthetically labeled by [3H]mannose, [3H]palmitic acid, and [32P]phosphorus. PLM has also been shown to be released from the C. albicans cell wall and to bind to and stimulate macrophage cells. In this study, we show by thin layer chromatography scanning of metabolically radiolabeled extracts that the C. albicans PLM corresponds to a family of mannose and inositol co-labeled glycolipids. We describe the purification process of the molecule and the release of its glycan fraction through alkaline hydrolysis. Analysis of this glycan fraction by radiolabeling and methylation-methanolysis confirmed the presence of inositol and of 1,2-linked mannose units. NMR studies evidenced linear chains of β-1,2-oligomannose as the major PLM components. Mass spectrometry analysis revealed that these chains were present in phosphoinositolmannosides with degrees of polymerization varying from 8 to 18 sugar residues. The PLM appears as a new type of eukaryotic inositol-tagged glycolipid in relationship to both the absence of glucosamine and the organization of its glycan chains. This first structural evidence for the presence of β-1,2-oligomannosides in a glycoconjugate other than the C. albicansphosphopeptidomannan may have some pathophysiological relevance to the adhesive, protective epitope, and signaling properties thus far established for these residues. In a series of studies, we have shown thatCandida albicans synthesizes a glycolipid, phospholipomannan (PLM), which reacted with antibodies specific for β-1,2-oligomannosides and was biosynthetically labeled by [3H]mannose, [3H]palmitic acid, and [32P]phosphorus. PLM has also been shown to be released from the C. albicans cell wall and to bind to and stimulate macrophage cells. In this study, we show by thin layer chromatography scanning of metabolically radiolabeled extracts that the C. albicans PLM corresponds to a family of mannose and inositol co-labeled glycolipids. We describe the purification process of the molecule and the release of its glycan fraction through alkaline hydrolysis. Analysis of this glycan fraction by radiolabeling and methylation-methanolysis confirmed the presence of inositol and of 1,2-linked mannose units. NMR studies evidenced linear chains of β-1,2-oligomannose as the major PLM components. Mass spectrometry analysis revealed that these chains were present in phosphoinositolmannosides with degrees of polymerization varying from 8 to 18 sugar residues. The PLM appears as a new type of eukaryotic inositol-tagged glycolipid in relationship to both the absence of glucosamine and the organization of its glycan chains. This first structural evidence for the presence of β-1,2-oligomannosides in a glycoconjugate other than the C. albicansphosphopeptidomannan may have some pathophysiological relevance to the adhesive, protective epitope, and signaling properties thus far established for these residues. tumor necrosis factor phospholipomannan thin layer chromatography gas chromatography/mass spectrometry matrix-assisted laser desorption/ionization time-of-flight monoclonal antibody glycosylphosphatidylinositol degrees of polymerization fraction The yeast Candida albicans is a normal component of the human endogenous microflora, but it can cause frequent and severe disseminated infections among hospitalized patients (1Pfaller M.A. Jones R.N. Messer S.A. Edmond M.B. Wenzel R.P. Diagn. Microbiol. Infect. Dis. 1998; 31: 327-332Crossref PubMed Scopus (288) Google Scholar). Basic progress has been made in the elucidation of C. albicanscharacteristics linked to switching (2Soll D.R. Microbiology. 1997; 143: 279-288Crossref PubMed Scopus (81) Google Scholar), dimorphism (3Leberer E. Ziegelbauer K. Schmidt A. Harcus D. Dignard D. Ash J. Johnson L. Thomas D.Y. Curr. Biol. 1997; 7: 539-546Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar), adhesion (4Gale C.A. Bendel C.M. McClellan M. Hauser M. Becker J.M. Berman J. Hostetter M.K. Science. 1998; 279: 1355-1358Crossref PubMed Scopus (306) Google Scholar), and enzyme secretion (5De Bernardis F. Boccanera M. Adriani D. Spreghini E. Santoni G. Cassone A. Infect. Immun. 1997; 65: 3399-3405Crossref PubMed Google Scholar, 6Ibrahim A.S. Mirbod F. Filler S.G. Banno Y. Cole G.T. Kitajima Y. Edwards Jr., J.E. Nozawa Y. Ghannoum M.A. Infect. Immun. 1995; 63: 1993-1998Crossref PubMed Google Scholar) that could explain the mechanism by which this fungus can be an opportunistic pathogen. However, the mechanisms that direct susceptibility and resistance to C. albicansinfection are as yet unclear, and current extensive research concernsC. albicans molecules interacting with the host immune system. Among these studies, research has gradually focused on β-1,2-linked oligomannosides. Oligomannnosides with this unusual type of linkage were first described by Shibata et al. (7Shibata N. Ichikawa T. Tojo M. Takahashi M. Ito N. Ohkubo Y. Suzuki S. Arch. Biochem. Biophys. 1985; 243: 338-348Crossref PubMed Scopus (98) Google Scholar) as associated with the C. albicans cell wall phosphopeptidomannan by phosphodiester bridges. β-1,2-oligomannosides are immunogenic and elicit specific antibodies in animals (8Faille C. Michalski J. Strecker G. Mackenzie D.W. Camus D. Poulain D. Infect. Immun. 1990; 58: 3537-3544Crossref PubMed Google Scholar, 9Shibata N. Arai M. Haga E. Kikuchi T. Najima M. Satoh T. Kobayashi H. Suzuki S. Infect. Immun. 1992; 60: 4100-4110Crossref PubMed Google Scholar, 10Tojo M. Shibata N. Kobayashi M. Mikami T. Suzuki M. Suzuki S. Clin. Chem. 1988; 34: 539-543Crossref PubMed Scopus (23) Google Scholar) and humans (11Poulain D. Faille C. Delannoy C. Jacquinot P.M. Trinel P.A. Camus D. Infect. Immun. 1993; 61: 1164-1166Crossref PubMed Google Scholar). Anti-β-1,2-oligomannosides antibodies have been shown to be protective against C. albicans in rodent models of systemic and vaginal candidosis (5De Bernardis F. Boccanera M. Adriani D. Spreghini E. Santoni G. Cassone A. Infect. Immun. 1997; 65: 3399-3405Crossref PubMed Google Scholar, 12Caesar-TonThat T.-C. Cutler J.E. Infect. Immun. 1997; 65: 5354-5357Crossref PubMed Google Scholar). β-1,2-oligomannosides derived from C. albicans phosphopeptidomannan have also been shown to induce TNF1-α synthesis from cells of the macrophage lineage through a phosphotyrosine kinase-dependent pathway (13Jouault T. Lepage G. Bernigaud A. Trinel P.A. Fradin C. Wieruszeski J.M. Strecker G. Poulain D. Infect. Immun. 1995; 63: 2378-2381Crossref PubMed Google Scholar) and to bind to macrophage cell membranes (14Li R.K. Cutler J.E. J. Biol. Chem. 1993; 268: 18293-18299Abstract Full Text PDF PubMed Google Scholar, 15Fradin C. Jouault T. Mallet A. Mallet J. Camus D. Sinaÿ P. Poulain D. J. Leukocyte Biol. 1996; 60: 81-87Crossref PubMed Scopus (73) Google Scholar).In previous studies, we have shown by use of specific monoclonal antibodies (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar) that β-1,2-oligomannosides are present (in the absence of accessible α-linked mannose residues) on a polydispersed low molecular weight antigen and that this antigen is a glycolipid. This glycolipid has been named a phospholipomannan (PLM) on the basis of its composition (17Trinel P.A. Borg-von-Zepelin M. Lepage G. Jouault T. Mackenzie D. Poulain D. Infect. Immun. 1993; 61: 4398-4405Crossref PubMed Google Scholar). The PLM is a strong TNF-α inducer in vitro and in vivo (18Jouault T. Bernigaud A. Lepage G. Trinel P. Poulain D. Immunology. 1994; 83: 268-273PubMed Google Scholar). When C. albicanscomes into contact with macrophages, large amounts of PLM are rapidly shed by C. albicans, which trigger intense signaling and secretory responses from these target cells (19Jouault T. Fradin C. Trinel P.A. Bernigaud A. Poulain D. J. Infect. Dis. 1998; 178: 792-802Crossref PubMed Scopus (49) Google Scholar). Similar signaling events induced in host cells have been described as induced by GPI-related glycolipids from pathogens of the generaLeishmania, Trypanosoma, andMycobacteria (20Schofield L. Tachado S. Immunol. Cell Biol. 1996; 74: 555-563Crossref PubMed Scopus (49) Google Scholar, 21Barnes P.F. Chatterjee D. Abrams J.S. Lu S. Wang E. Yamamura M. Brennan P.J. Modlin R.L. J. Immunol. 1992; 149: 541-547PubMed Google Scholar, 22Dahl K.E. Shiratsuchi H. Hamilton B.D. Ellner J.J. Toossi Z. Infect. Immun. 1996; 64: 399-405Crossref PubMed Google Scholar, 23Yoshida A. Koide Y. Infect. Immun. 1997; 65: 1953-1955Crossref PubMed Google Scholar). In this study, we have further purified and chemically analyzed the C. albicans PLM to establish the relationship of PLM with these microbiolglycolipids and to provide a structural basis for the understanding of the immunochemical and immunomodulatory properties of PLM.DISCUSSIONUnlike α-mannosides, which are widely expressed on glycoconjugates, the rarity of β-mannosides may be explained by a less favorable stereochemistry. To date, homopolymers of β-1,2-linked mannose have been chemically characterized only in imperfect yeasts of the genus Candida (related to Ascomycetes). They are associated to side chains of the cell wall phosphopeptidomannan ofC. albicans and C. tropicalis through phosphodiester bridges (7Shibata N. Ichikawa T. Tojo M. Takahashi M. Ito N. Ohkubo Y. Suzuki S. Arch. Biochem. Biophys. 1985; 243: 338-348Crossref PubMed Scopus (98) Google Scholar, 31Kobayashi H. Matsuda K. Ikeda T. Suzuki M. Takahashi S.H. Suzuki A. Shibata N. Suzuki S. Infect. Immun. 1994; 62: 615-622Crossref PubMed Google Scholar). NMR analysis of these residues released from C. albicans phosphopeptidomannan by mild acid hydrolysis has also shown changes in their ratios and degrees of polymerization, depending on the strains (7Shibata N. Ichikawa T. Tojo M. Takahashi M. Ito N. Ohkubo Y. Suzuki S. Arch. Biochem. Biophys. 1985; 243: 338-348Crossref PubMed Scopus (98) Google Scholar, 31Kobayashi H. Matsuda K. Ikeda T. Suzuki M. Takahashi S.H. Suzuki A. Shibata N. Suzuki S. Infect. Immun. 1994; 62: 615-622Crossref PubMed Google Scholar), the cell form (32Shibata N. Kobayashi H. Tojo M. Suzuki S. Arch. Biochem. Biophys. 1986; 251: 697-708Crossref PubMed Scopus (54) Google Scholar,33Shibata N. Fukasawa S. Kobayashi H. Tojo M. Yonezu T. Ambo A. Ohkubo Y. Suzuki S. Carbohydr. Res. 1989; 187: 239-253Crossref PubMed Scopus (77) Google Scholar), and the growth conditions (34Kobayashi H. Giummelly P. Takahashi S. Ishida M. Sato J. Takaku M. Nishidate Y. Shibata N. Okawa Y. Suzuki S. Biochem. Biophys. Res. Commun. 1991; 5: 1003-1009Crossref Scopus (44) Google Scholar, 35Okawa Y. Takahata T. Kawamata M. Miyauchi M. Shibata N. Suzuki A. Kobayashi H. Suzuki S. FEBS Lett. 1994; 45: 167-171Crossref Scopus (36) Google Scholar).In relation to the pathogenic character of C. albicans, several groups have investigated the recognition of β-1,2-oligomannosides by immune systems. These molecules have been shown to elicit specific antibodies in mice (36Cassone A. Torosantucci A. Boccanera M. Pellegrini G., C., P. Malvasi F. J. Med. Microbiol. 1988; 27: 233-238Crossref PubMed Scopus (47) Google Scholar), rats (37Hopwood V. Poulain D. Fortier B. Evans G. Vernes A. Infect. Immun. 1986; 54: 222-227Crossref PubMed Google Scholar), rabbits (9Shibata N. Arai M. Haga E. Kikuchi T. Najima M. Satoh T. Kobayashi H. Suzuki S. Infect. Immun. 1992; 60: 4100-4110Crossref PubMed Google Scholar), and humans (11Poulain D. Faille C. Delannoy C. Jacquinot P.M. Trinel P.A. Camus D. Infect. Immun. 1993; 61: 1164-1166Crossref PubMed Google Scholar, 38Hernando F. Cailliez J.C. Trinel P.A. Faille C. Mackenzie D. Poulain D. J. Med. Vet. Mycol. 1993; 31: 219-226Crossref PubMed Scopus (10) Google Scholar). The construction of neoglycolipids with phosphopeptidomannan-released β-1,2-oligomannosides has demonstrated that they can act as epitopes for a large number of anti-C. albicans phosphopeptidomannan monoclonal antibodies (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar), suggesting that C. albicans mannoglycoconjugate(s) expressing these residues are strong immunogens. Two anti-β-1,2-oligomannosides monoclonal antibodies have been described as protective against experimental C. albicans infection. The first one, reacting with a β-1,2-linked mannotriose, protected mice in a systemic model of candidosis (12Caesar-TonThat T.-C. Cutler J.E. Infect. Immun. 1997; 65: 5354-5357Crossref PubMed Google Scholar). The second one protected rats in a model of vaginal infection (5De Bernardis F. Boccanera M. Adriani D. Spreghini E. Santoni G. Cassone A. Infect. Immun. 1997; 65: 3399-3405Crossref PubMed Google Scholar). When we analyzed C. albicans molecules expressing β-1,2-oligomannosidic epitopes, we observed that all polyclonal or monoclonal antibodies specific for these residues bound to a 14–18-kDa antigen that did not display accessible α-linked mannose residues (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar). This antigen, named phopholipomannan (17Trinel P.A. Borg-von-Zepelin M. Lepage G. Jouault T. Mackenzie D. Poulain D. Infect. Immun. 1993; 61: 4398-4405Crossref PubMed Google Scholar), is expressed only in C. albicans andC. tropicalis, which are the most pathogenicCandida species (25Cantelli C. Trinel P.A. Bernigaud A. Jouault T. Polonelli L. Poulain D. Microbiology. 1995; 141: 2693-2697Crossref PubMed Scopus (17) Google Scholar). PLM is synthesized by C. albicans including under growth conditions that prevent association of β-1,2-linked oligomannosides to phosphopeptidomannan (30Trinel P. Cantelli C. Bernigaud A. Jouault T. Poulain D. Microbiology. 1996; 142: 2263-2270Crossref PubMed Scopus (13) Google Scholar). Recent experiments have shown that C. albicans, in contact with macrophages, shed large amounts of PLM, which triggers an intense phosphotyrosine kinase-dependent signaling pathway and the secretion of TNF-α (19Jouault T. Fradin C. Trinel P.A. Bernigaud A. Poulain D. J. Infect. Dis. 1998; 178: 792-802Crossref PubMed Scopus (49) Google Scholar). The synthesis of surface glycolipids that protect from host defenses and/or disturb host cell immune functions is recognized as a pathogenic characteristic of eukaryotic protozoa of the genera Leishmania and Trypanosoma(20Schofield L. Tachado S. Immunol. Cell Biol. 1996; 74: 555-563Crossref PubMed Scopus (49) Google Scholar) and of prokaryotes of the genus Mycobacteria(21Barnes P.F. Chatterjee D. Abrams J.S. Lu S. Wang E. Yamamura M. Brennan P.J. Modlin R.L. J. Immunol. 1992; 149: 541-547PubMed Google Scholar, 22Dahl K.E. Shiratsuchi H. Hamilton B.D. Ellner J.J. Toossi Z. Infect. Immun. 1996; 64: 399-405Crossref PubMed Google Scholar, 23Yoshida A. Koide Y. Infect. Immun. 1997; 65: 1953-1955Crossref PubMed Google Scholar).In this study we analyzed PLM to obtain chemical evidence for the presence of β-1,2-oligomannosides and to assess the possible structural relationships with surface glycolipids of these other microbial pathogens. Like these glycolipids, the C. albicansPLM was metabolically labeled by [3H]mannose and [3H]inositol, and both labeling profiles were superimposed in a family of hydrophilic glycolipids with β-1,2-oligomannosidic epitopes. The physicochemical analysis of the PLM sugar moiety confirmed the presence of mannose and inositol and evidenced the absence of glucosamine. The absence of this residue is consistent with the PLM resistance to nitrous acid treatment (29Ferguson M.A.J. Fukuda M. Kobata A. Glycobiology: A Practical Approach. IRL Press, Oxford, UK1993: 349-384Google Scholar) and its unlabeling with [3H]glucosamine (unpublished data). Glucosamine linking inositol to the sugar moiety is a common feature of GPI and GPI-related glycolipids (39McConville M.J. Ferguson M.A.J. Biochem. J. 1993; 294: 305-324Crossref PubMed Scopus (798) Google Scholar) of eukaryotic cells. Its absence has only been reported to date in lipoarabinomannan, a GPI-like structure from prokaryotes of the genus Mycobacteria. Another peculiarity of PLM lies in the exclusive presence of β-1,2-linked mannose residues in its sugar moiety, which were found to be organized in linear chains with degrees of polymerization ranging from 8 to 18. Confirmation of the probable presence of a Man-1-phosphate linkage in the molecule, as deduced from NMR spectrum, will require further studies.The average mass of PLM may be estimated, from the present study, to be about 4 kDa. This mass is different from the former description of the PLM as corresponding to a C. albicans 14–18-kDa antigen in Western blotting (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar). By using more reticulated gels (7–20% acrylamide) and migration conditions favoring the progressive blockage of the molecules in the gel rather than their migration speed, we observed that the PLM relative molecular mass upon SDS-PAGE decreased to 7 kDa (data not shown).In Fig. 7 we suggest a structural model for the PLM glycan moiety, based on the first chemical evidence for the presence of β-1,2-linked oligomannosides in a glycoconjugate other than the yeast phosphopeptidomannan. Very little is known about β-1,2-mannosyltransferases of C. albicans, their activation and substrate specificity, but the presence of such linear chains of up to 18 mannose residues represent quite unusual structures (24Trinel P.A. Lepage G. Jouault T. Strecker G. Poulain D. FEBS Lett. 1997; 416: 203-206Crossref PubMed Scopus (29) Google Scholar). It has been suggested that a consequence of coating parasite surfaces with long sugar chains is the triggering of host effector mechanisms at a distance too great for efficient antimicrobial activity on the parasite. The recent demonstration for the presence of PLM at the C. albicans cell wall surface (19Jouault T. Fradin C. Trinel P.A. Bernigaud A. Poulain D. J. Infect. Dis. 1998; 178: 792-802Crossref PubMed Scopus (49) Google Scholar) suggests that these mechanisms may play a role during host-C. albicansinteraction. Moreover, β-1,2-oligomannosides have been shown to act as C. albicans adhesins for the macrophage membrane (15Fradin C. Jouault T. Mallet A. Mallet J. Camus D. Sinaÿ P. Poulain D. J. Leukocyte Biol. 1996; 60: 81-87Crossref PubMed Scopus (73) Google Scholar) and to stimulate macrophages to produce high levels of TNF-α (13Jouault T. Lepage G. Bernigaud A. Trinel P.A. Fradin C. Wieruszeski J.M. Strecker G. Poulain D. Infect. Immun. 1995; 63: 2378-2381Crossref PubMed Google Scholar, 18Jouault T. Bernigaud A. Lepage G. Trinel P. Poulain D. Immunology. 1994; 83: 268-273PubMed Google Scholar). The stimulating activity of β-1,2-oligomannosides was found to depend on the length of the mannosyl chain and maximum activity was observed for DPs of 8 or higher (13Jouault T. Lepage G. Bernigaud A. Trinel P.A. Fradin C. Wieruszeski J.M. Strecker G. Poulain D. Infect. Immun. 1995; 63: 2378-2381Crossref PubMed Google Scholar). Interestingly, these high DPs are present mainly in the C. albicans PLM but correspond to minor components among the β-1,2-oligomannosides released from the mannan of the same species (24Trinel P.A. Lepage G. Jouault T. Strecker G. Poulain D. FEBS Lett. 1997; 416: 203-206Crossref PubMed Scopus (29) Google Scholar).In conclusion, we have shown that the pathogenic yeast C. albicans synthesizes inositol-labeled glycolipids that have glycan moieties devoid of glucosamine. These C. albicansglycolipids are thus structurally more similar to lipoarabinomannans ofMycobacteria than to the glycosylinositolphospholipids of parasitic protozoa or the lipophosphoglycan of Leishmania. Recently, as well as being B cell antigens, mannose sequences of lipoarabinomannan have been implicated in the presentation to T cells by CD1b nonclassical major histocompatibility complex molecules (40Prigozy T.I. Seiling P.A. Clemens D. Stewart P.L. Behar S.M. Porcelli S.A. Brenner M.B. Modlin R.L. Kronenberg M. Immunity. 1997; 6: 187-197Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar). Whether or not this property is shared by C. albicans PLM remains to be investigated. An important PLM structural peculiarity lies in the presence of long chains of β-1,2-linked mannose residues. There is now considerable experimental evidence that these sugar residues are involved in virulence and immunomodulation and can elicit protective antibody responses. Therefore, PLMs are molecules that must be considered for a comprehensive analysis of host-C. albicans relationships. A complete elucidation of their structure and biosynthetic pathways will be necessary to provide a structural basis for understanding their immunochemical properties and some aspects of the pathogenesis of C. albicans infections. The yeast Candida albicans is a normal component of the human endogenous microflora, but it can cause frequent and severe disseminated infections among hospitalized patients (1Pfaller M.A. Jones R.N. Messer S.A. Edmond M.B. Wenzel R.P. Diagn. Microbiol. Infect. Dis. 1998; 31: 327-332Crossref PubMed Scopus (288) Google Scholar). Basic progress has been made in the elucidation of C. albicanscharacteristics linked to switching (2Soll D.R. Microbiology. 1997; 143: 279-288Crossref PubMed Scopus (81) Google Scholar), dimorphism (3Leberer E. Ziegelbauer K. Schmidt A. Harcus D. Dignard D. Ash J. Johnson L. Thomas D.Y. Curr. Biol. 1997; 7: 539-546Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar), adhesion (4Gale C.A. Bendel C.M. McClellan M. Hauser M. Becker J.M. Berman J. Hostetter M.K. Science. 1998; 279: 1355-1358Crossref PubMed Scopus (306) Google Scholar), and enzyme secretion (5De Bernardis F. Boccanera M. Adriani D. Spreghini E. Santoni G. Cassone A. Infect. Immun. 1997; 65: 3399-3405Crossref PubMed Google Scholar, 6Ibrahim A.S. Mirbod F. Filler S.G. Banno Y. Cole G.T. Kitajima Y. Edwards Jr., J.E. Nozawa Y. Ghannoum M.A. Infect. Immun. 1995; 63: 1993-1998Crossref PubMed Google Scholar) that could explain the mechanism by which this fungus can be an opportunistic pathogen. However, the mechanisms that direct susceptibility and resistance to C. albicansinfection are as yet unclear, and current extensive research concernsC. albicans molecules interacting with the host immune system. Among these studies, research has gradually focused on β-1,2-linked oligomannosides. Oligomannnosides with this unusual type of linkage were first described by Shibata et al. (7Shibata N. Ichikawa T. Tojo M. Takahashi M. Ito N. Ohkubo Y. Suzuki S. Arch. Biochem. Biophys. 1985; 243: 338-348Crossref PubMed Scopus (98) Google Scholar) as associated with the C. albicans cell wall phosphopeptidomannan by phosphodiester bridges. β-1,2-oligomannosides are immunogenic and elicit specific antibodies in animals (8Faille C. Michalski J. Strecker G. Mackenzie D.W. Camus D. Poulain D. Infect. Immun. 1990; 58: 3537-3544Crossref PubMed Google Scholar, 9Shibata N. Arai M. Haga E. Kikuchi T. Najima M. Satoh T. Kobayashi H. Suzuki S. Infect. Immun. 1992; 60: 4100-4110Crossref PubMed Google Scholar, 10Tojo M. Shibata N. Kobayashi M. Mikami T. Suzuki M. Suzuki S. Clin. Chem. 1988; 34: 539-543Crossref PubMed Scopus (23) Google Scholar) and humans (11Poulain D. Faille C. Delannoy C. Jacquinot P.M. Trinel P.A. Camus D. Infect. Immun. 1993; 61: 1164-1166Crossref PubMed Google Scholar). Anti-β-1,2-oligomannosides antibodies have been shown to be protective against C. albicans in rodent models of systemic and vaginal candidosis (5De Bernardis F. Boccanera M. Adriani D. Spreghini E. Santoni G. Cassone A. Infect. Immun. 1997; 65: 3399-3405Crossref PubMed Google Scholar, 12Caesar-TonThat T.-C. Cutler J.E. Infect. Immun. 1997; 65: 5354-5357Crossref PubMed Google Scholar). β-1,2-oligomannosides derived from C. albicans phosphopeptidomannan have also been shown to induce TNF1-α synthesis from cells of the macrophage lineage through a phosphotyrosine kinase-dependent pathway (13Jouault T. Lepage G. Bernigaud A. Trinel P.A. Fradin C. Wieruszeski J.M. Strecker G. Poulain D. Infect. Immun. 1995; 63: 2378-2381Crossref PubMed Google Scholar) and to bind to macrophage cell membranes (14Li R.K. Cutler J.E. J. Biol. Chem. 1993; 268: 18293-18299Abstract Full Text PDF PubMed Google Scholar, 15Fradin C. Jouault T. Mallet A. Mallet J. Camus D. Sinaÿ P. Poulain D. J. Leukocyte Biol. 1996; 60: 81-87Crossref PubMed Scopus (73) Google Scholar). In previous studies, we have shown by use of specific monoclonal antibodies (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar) that β-1,2-oligomannosides are present (in the absence of accessible α-linked mannose residues) on a polydispersed low molecular weight antigen and that this antigen is a glycolipid. This glycolipid has been named a phospholipomannan (PLM) on the basis of its composition (17Trinel P.A. Borg-von-Zepelin M. Lepage G. Jouault T. Mackenzie D. Poulain D. Infect. Immun. 1993; 61: 4398-4405Crossref PubMed Google Scholar). The PLM is a strong TNF-α inducer in vitro and in vivo (18Jouault T. Bernigaud A. Lepage G. Trinel P. Poulain D. Immunology. 1994; 83: 268-273PubMed Google Scholar). When C. albicanscomes into contact with macrophages, large amounts of PLM are rapidly shed by C. albicans, which trigger intense signaling and secretory responses from these target cells (19Jouault T. Fradin C. Trinel P.A. Bernigaud A. Poulain D. J. Infect. Dis. 1998; 178: 792-802Crossref PubMed Scopus (49) Google Scholar). Similar signaling events induced in host cells have been described as induced by GPI-related glycolipids from pathogens of the generaLeishmania, Trypanosoma, andMycobacteria (20Schofield L. Tachado S. Immunol. Cell Biol. 1996; 74: 555-563Crossref PubMed Scopus (49) Google Scholar, 21Barnes P.F. Chatterjee D. Abrams J.S. Lu S. Wang E. Yamamura M. Brennan P.J. Modlin R.L. J. Immunol. 1992; 149: 541-547PubMed Google Scholar, 22Dahl K.E. Shiratsuchi H. Hamilton B.D. Ellner J.J. Toossi Z. Infect. Immun. 1996; 64: 399-405Crossref PubMed Google Scholar, 23Yoshida A. Koide Y. Infect. Immun. 1997; 65: 1953-1955Crossref PubMed Google Scholar). In this study, we have further purified and chemically analyzed the C. albicans PLM to establish the relationship of PLM with these microbiolglycolipids and to provide a structural basis for the understanding of the immunochemical and immunomodulatory properties of PLM. DISCUSSIONUnlike α-mannosides, which are widely expressed on glycoconjugates, the rarity of β-mannosides may be explained by a less favorable stereochemistry. To date, homopolymers of β-1,2-linked mannose have been chemically characterized only in imperfect yeasts of the genus Candida (related to Ascomycetes). They are associated to side chains of the cell wall phosphopeptidomannan ofC. albicans and C. tropicalis through phosphodiester bridges (7Shibata N. Ichikawa T. Tojo M. Takahashi M. Ito N. Ohkubo Y. Suzuki S. Arch. Biochem. Biophys. 1985; 243: 338-348Crossref PubMed Scopus (98) Google Scholar, 31Kobayashi H. Matsuda K. Ikeda T. Suzuki M. Takahashi S.H. Suzuki A. Shibata N. Suzuki S. Infect. Immun. 1994; 62: 615-622Crossref PubMed Google Scholar). NMR analysis of these residues released from C. albicans phosphopeptidomannan by mild acid hydrolysis has also shown changes in their ratios and degrees of polymerization, depending on the strains (7Shibata N. Ichikawa T. Tojo M. Takahashi M. Ito N. Ohkubo Y. Suzuki S. Arch. Biochem. Biophys. 1985; 243: 338-348Crossref PubMed Scopus (98) Google Scholar, 31Kobayashi H. Matsuda K. Ikeda T. Suzuki M. Takahashi S.H. Suzuki A. Shibata N. Suzuki S. Infect. Immun. 1994; 62: 615-622Crossref PubMed Google Scholar), the cell form (32Shibata N. Kobayashi H. Tojo M. Suzuki S. Arch. Biochem. Biophys. 1986; 251: 697-708Crossref PubMed Scopus (54) Google Scholar,33Shibata N. Fukasawa S. Kobayashi H. Tojo M. Yonezu T. Ambo A. Ohkubo Y. Suzuki S. Carbohydr. Res. 1989; 187: 239-253Crossref PubMed Scopus (77) Google Scholar), and the growth conditions (34Kobayashi H. Giummelly P. Takahashi S. Ishida M. Sato J. Takaku M. Nishidate Y. Shibata N. Okawa Y. Suzuki S. Biochem. Biophys. Res. Commun. 1991; 5: 1003-1009Crossref Scopus (44) Google Scholar, 35Okawa Y. Takahata T. Kawamata M. Miyauchi M. Shibata N. Suzuki A. Kobayashi H. Suzuki S. FEBS Lett. 1994; 45: 167-171Crossref Scopus (36) Google Scholar).In relation to the pathogenic character of C. albicans, several groups have investigated the recognition of β-1,2-oligomannosides by immune systems. These molecules have been shown to elicit specific antibodies in mice (36Cassone A. Torosantucci A. Boccanera M. Pellegrini G., C., P. Malvasi F. J. Med. Microbiol. 1988; 27: 233-238Crossref PubMed Scopus (47) Google Scholar), rats (37Hopwood V. Poulain D. Fortier B. Evans G. Vernes A. Infect. Immun. 1986; 54: 222-227Crossref PubMed Google Scholar), rabbits (9Shibata N. Arai M. Haga E. Kikuchi T. Najima M. Satoh T. Kobayashi H. Suzuki S. Infect. Immun. 1992; 60: 4100-4110Crossref PubMed Google Scholar), and humans (11Poulain D. Faille C. Delannoy C. Jacquinot P.M. Trinel P.A. Camus D. Infect. Immun. 1993; 61: 1164-1166Crossref PubMed Google Scholar, 38Hernando F. Cailliez J.C. Trinel P.A. Faille C. Mackenzie D. Poulain D. J. Med. Vet. Mycol. 1993; 31: 219-226Crossref PubMed Scopus (10) Google Scholar). The construction of neoglycolipids with phosphopeptidomannan-released β-1,2-oligomannosides has demonstrated that they can act as epitopes for a large number of anti-C. albicans phosphopeptidomannan monoclonal antibodies (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar), suggesting that C. albicans mannoglycoconjugate(s) expressing these residues are strong immunogens. Two anti-β-1,2-oligomannosides monoclonal antibodies have been described as protective against experimental C. albicans infection. The first one, reacting with a β-1,2-linked mannotriose, protected mice in a systemic model of candidosis (12Caesar-TonThat T.-C. Cutler J.E. Infect. Immun. 1997; 65: 5354-5357Crossref PubMed Google Scholar). The second one protected rats in a model of vaginal infection (5De Bernardis F. Boccanera M. Adriani D. Spreghini E. Santoni G. Cassone A. Infect. Immun. 1997; 65: 3399-3405Crossref PubMed Google Scholar). When we analyzed C. albicans molecules expressing β-1,2-oligomannosidic epitopes, we observed that all polyclonal or monoclonal antibodies specific for these residues bound to a 14–18-kDa antigen that did not display accessible α-linked mannose residues (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar). This antigen, named phopholipomannan (17Trinel P.A. Borg-von-Zepelin M. Lepage G. Jouault T. Mackenzie D. Poulain D. Infect. Immun. 1993; 61: 4398-4405Crossref PubMed Google Scholar), is expressed only in C. albicans andC. tropicalis, which are the most pathogenicCandida species (25Cantelli C. Trinel P.A. Bernigaud A. Jouault T. Polonelli L. Poulain D. Microbiology. 1995; 141: 2693-2697Crossref PubMed Scopus (17) Google Scholar). PLM is synthesized by C. albicans including under growth conditions that prevent association of β-1,2-linked oligomannosides to phosphopeptidomannan (30Trinel P. Cantelli C. Bernigaud A. Jouault T. Poulain D. Microbiology. 1996; 142: 2263-2270Crossref PubMed Scopus (13) Google Scholar). Recent experiments have shown that C. albicans, in contact with macrophages, shed large amounts of PLM, which triggers an intense phosphotyrosine kinase-dependent signaling pathway and the secretion of TNF-α (19Jouault T. Fradin C. Trinel P.A. Bernigaud A. Poulain D. J. Infect. Dis. 1998; 178: 792-802Crossref PubMed Scopus (49) Google Scholar). The synthesis of surface glycolipids that protect from host defenses and/or disturb host cell immune functions is recognized as a pathogenic characteristic of eukaryotic protozoa of the genera Leishmania and Trypanosoma(20Schofield L. Tachado S. Immunol. Cell Biol. 1996; 74: 555-563Crossref PubMed Scopus (49) Google Scholar) and of prokaryotes of the genus Mycobacteria(21Barnes P.F. Chatterjee D. Abrams J.S. Lu S. Wang E. Yamamura M. Brennan P.J. Modlin R.L. J. Immunol. 1992; 149: 541-547PubMed Google Scholar, 22Dahl K.E. Shiratsuchi H. Hamilton B.D. Ellner J.J. Toossi Z. Infect. Immun. 1996; 64: 399-405Crossref PubMed Google Scholar, 23Yoshida A. Koide Y. Infect. Immun. 1997; 65: 1953-1955Crossref PubMed Google Scholar).In this study we analyzed PLM to obtain chemical evidence for the presence of β-1,2-oligomannosides and to assess the possible structural relationships with surface glycolipids of these other microbial pathogens. Like these glycolipids, the C. albicansPLM was metabolically labeled by [3H]mannose and [3H]inositol, and both labeling profiles were superimposed in a family of hydrophilic glycolipids with β-1,2-oligomannosidic epitopes. The physicochemical analysis of the PLM sugar moiety confirmed the presence of mannose and inositol and evidenced the absence of glucosamine. The absence of this residue is consistent with the PLM resistance to nitrous acid treatment (29Ferguson M.A.J. Fukuda M. Kobata A. Glycobiology: A Practical Approach. IRL Press, Oxford, UK1993: 349-384Google Scholar) and its unlabeling with [3H]glucosamine (unpublished data). Glucosamine linking inositol to the sugar moiety is a common feature of GPI and GPI-related glycolipids (39McConville M.J. Ferguson M.A.J. Biochem. J. 1993; 294: 305-324Crossref PubMed Scopus (798) Google Scholar) of eukaryotic cells. Its absence has only been reported to date in lipoarabinomannan, a GPI-like structure from prokaryotes of the genus Mycobacteria. Another peculiarity of PLM lies in the exclusive presence of β-1,2-linked mannose residues in its sugar moiety, which were found to be organized in linear chains with degrees of polymerization ranging from 8 to 18. Confirmation of the probable presence of a Man-1-phosphate linkage in the molecule, as deduced from NMR spectrum, will require further studies.The average mass of PLM may be estimated, from the present study, to be about 4 kDa. This mass is different from the former description of the PLM as corresponding to a C. albicans 14–18-kDa antigen in Western blotting (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar). By using more reticulated gels (7–20% acrylamide) and migration conditions favoring the progressive blockage of the molecules in the gel rather than their migration speed, we observed that the PLM relative molecular mass upon SDS-PAGE decreased to 7 kDa (data not shown).In Fig. 7 we suggest a structural model for the PLM glycan moiety, based on the first chemical evidence for the presence of β-1,2-linked oligomannosides in a glycoconjugate other than the yeast phosphopeptidomannan. Very little is known about β-1,2-mannosyltransferases of C. albicans, their activation and substrate specificity, but the presence of such linear chains of up to 18 mannose residues represent quite unusual structures (24Trinel P.A. Lepage G. Jouault T. Strecker G. Poulain D. FEBS Lett. 1997; 416: 203-206Crossref PubMed Scopus (29) Google Scholar). It has been suggested that a consequence of coating parasite surfaces with long sugar chains is the triggering of host effector mechanisms at a distance too great for efficient antimicrobial activity on the parasite. The recent demonstration for the presence of PLM at the C. albicans cell wall surface (19Jouault T. Fradin C. Trinel P.A. Bernigaud A. Poulain D. J. Infect. Dis. 1998; 178: 792-802Crossref PubMed Scopus (49) Google Scholar) suggests that these mechanisms may play a role during host-C. albicansinteraction. Moreover, β-1,2-oligomannosides have been shown to act as C. albicans adhesins for the macrophage membrane (15Fradin C. Jouault T. Mallet A. Mallet J. Camus D. Sinaÿ P. Poulain D. J. Leukocyte Biol. 1996; 60: 81-87Crossref PubMed Scopus (73) Google Scholar) and to stimulate macrophages to produce high levels of TNF-α (13Jouault T. Lepage G. Bernigaud A. Trinel P.A. Fradin C. Wieruszeski J.M. Strecker G. Poulain D. Infect. Immun. 1995; 63: 2378-2381Crossref PubMed Google Scholar, 18Jouault T. Bernigaud A. Lepage G. Trinel P. Poulain D. Immunology. 1994; 83: 268-273PubMed Google Scholar). The stimulating activity of β-1,2-oligomannosides was found to depend on the length of the mannosyl chain and maximum activity was observed for DPs of 8 or higher (13Jouault T. Lepage G. Bernigaud A. Trinel P.A. Fradin C. Wieruszeski J.M. Strecker G. Poulain D. Infect. Immun. 1995; 63: 2378-2381Crossref PubMed Google Scholar). Interestingly, these high DPs are present mainly in the C. albicans PLM but correspond to minor components among the β-1,2-oligomannosides released from the mannan of the same species (24Trinel P.A. Lepage G. Jouault T. Strecker G. Poulain D. FEBS Lett. 1997; 416: 203-206Crossref PubMed Scopus (29) Google Scholar).In conclusion, we have shown that the pathogenic yeast C. albicans synthesizes inositol-labeled glycolipids that have glycan moieties devoid of glucosamine. These C. albicansglycolipids are thus structurally more similar to lipoarabinomannans ofMycobacteria than to the glycosylinositolphospholipids of parasitic protozoa or the lipophosphoglycan of Leishmania. Recently, as well as being B cell antigens, mannose sequences of lipoarabinomannan have been implicated in the presentation to T cells by CD1b nonclassical major histocompatibility complex molecules (40Prigozy T.I. Seiling P.A. Clemens D. Stewart P.L. Behar S.M. Porcelli S.A. Brenner M.B. Modlin R.L. Kronenberg M. Immunity. 1997; 6: 187-197Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar). Whether or not this property is shared by C. albicans PLM remains to be investigated. An important PLM structural peculiarity lies in the presence of long chains of β-1,2-linked mannose residues. There is now considerable experimental evidence that these sugar residues are involved in virulence and immunomodulation and can elicit protective antibody responses. Therefore, PLMs are molecules that must be considered for a comprehensive analysis of host-C. albicans relationships. A complete elucidation of their structure and biosynthetic pathways will be necessary to provide a structural basis for understanding their immunochemical properties and some aspects of the pathogenesis of C. albicans infections. Unlike α-mannosides, which are widely expressed on glycoconjugates, the rarity of β-mannosides may be explained by a less favorable stereochemistry. To date, homopolymers of β-1,2-linked mannose have been chemically characterized only in imperfect yeasts of the genus Candida (related to Ascomycetes). They are associated to side chains of the cell wall phosphopeptidomannan ofC. albicans and C. tropicalis through phosphodiester bridges (7Shibata N. Ichikawa T. Tojo M. Takahashi M. Ito N. Ohkubo Y. Suzuki S. Arch. Biochem. Biophys. 1985; 243: 338-348Crossref PubMed Scopus (98) Google Scholar, 31Kobayashi H. Matsuda K. Ikeda T. Suzuki M. Takahashi S.H. Suzuki A. Shibata N. Suzuki S. Infect. Immun. 1994; 62: 615-622Crossref PubMed Google Scholar). NMR analysis of these residues released from C. albicans phosphopeptidomannan by mild acid hydrolysis has also shown changes in their ratios and degrees of polymerization, depending on the strains (7Shibata N. Ichikawa T. Tojo M. Takahashi M. Ito N. Ohkubo Y. Suzuki S. Arch. Biochem. Biophys. 1985; 243: 338-348Crossref PubMed Scopus (98) Google Scholar, 31Kobayashi H. Matsuda K. Ikeda T. Suzuki M. Takahashi S.H. Suzuki A. Shibata N. Suzuki S. Infect. Immun. 1994; 62: 615-622Crossref PubMed Google Scholar), the cell form (32Shibata N. Kobayashi H. Tojo M. Suzuki S. Arch. Biochem. Biophys. 1986; 251: 697-708Crossref PubMed Scopus (54) Google Scholar,33Shibata N. Fukasawa S. Kobayashi H. Tojo M. Yonezu T. Ambo A. Ohkubo Y. Suzuki S. Carbohydr. Res. 1989; 187: 239-253Crossref PubMed Scopus (77) Google Scholar), and the growth conditions (34Kobayashi H. Giummelly P. Takahashi S. Ishida M. Sato J. Takaku M. Nishidate Y. Shibata N. Okawa Y. Suzuki S. Biochem. Biophys. Res. Commun. 1991; 5: 1003-1009Crossref Scopus (44) Google Scholar, 35Okawa Y. Takahata T. Kawamata M. Miyauchi M. Shibata N. Suzuki A. Kobayashi H. Suzuki S. FEBS Lett. 1994; 45: 167-171Crossref Scopus (36) Google Scholar). In relation to the pathogenic character of C. albicans, several groups have investigated the recognition of β-1,2-oligomannosides by immune systems. These molecules have been shown to elicit specific antibodies in mice (36Cassone A. Torosantucci A. Boccanera M. Pellegrini G., C., P. Malvasi F. J. Med. Microbiol. 1988; 27: 233-238Crossref PubMed Scopus (47) Google Scholar), rats (37Hopwood V. Poulain D. Fortier B. Evans G. Vernes A. Infect. Immun. 1986; 54: 222-227Crossref PubMed Google Scholar), rabbits (9Shibata N. Arai M. Haga E. Kikuchi T. Najima M. Satoh T. Kobayashi H. Suzuki S. Infect. Immun. 1992; 60: 4100-4110Crossref PubMed Google Scholar), and humans (11Poulain D. Faille C. Delannoy C. Jacquinot P.M. Trinel P.A. Camus D. Infect. Immun. 1993; 61: 1164-1166Crossref PubMed Google Scholar, 38Hernando F. Cailliez J.C. Trinel P.A. Faille C. Mackenzie D. Poulain D. J. Med. Vet. Mycol. 1993; 31: 219-226Crossref PubMed Scopus (10) Google Scholar). The construction of neoglycolipids with phosphopeptidomannan-released β-1,2-oligomannosides has demonstrated that they can act as epitopes for a large number of anti-C. albicans phosphopeptidomannan monoclonal antibodies (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar), suggesting that C. albicans mannoglycoconjugate(s) expressing these residues are strong immunogens. Two anti-β-1,2-oligomannosides monoclonal antibodies have been described as protective against experimental C. albicans infection. The first one, reacting with a β-1,2-linked mannotriose, protected mice in a systemic model of candidosis (12Caesar-TonThat T.-C. Cutler J.E. Infect. Immun. 1997; 65: 5354-5357Crossref PubMed Google Scholar). The second one protected rats in a model of vaginal infection (5De Bernardis F. Boccanera M. Adriani D. Spreghini E. Santoni G. Cassone A. Infect. Immun. 1997; 65: 3399-3405Crossref PubMed Google Scholar). When we analyzed C. albicans molecules expressing β-1,2-oligomannosidic epitopes, we observed that all polyclonal or monoclonal antibodies specific for these residues bound to a 14–18-kDa antigen that did not display accessible α-linked mannose residues (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar). This antigen, named phopholipomannan (17Trinel P.A. Borg-von-Zepelin M. Lepage G. Jouault T. Mackenzie D. Poulain D. Infect. Immun. 1993; 61: 4398-4405Crossref PubMed Google Scholar), is expressed only in C. albicans andC. tropicalis, which are the most pathogenicCandida species (25Cantelli C. Trinel P.A. Bernigaud A. Jouault T. Polonelli L. Poulain D. Microbiology. 1995; 141: 2693-2697Crossref PubMed Scopus (17) Google Scholar). PLM is synthesized by C. albicans including under growth conditions that prevent association of β-1,2-linked oligomannosides to phosphopeptidomannan (30Trinel P. Cantelli C. Bernigaud A. Jouault T. Poulain D. Microbiology. 1996; 142: 2263-2270Crossref PubMed Scopus (13) Google Scholar). Recent experiments have shown that C. albicans, in contact with macrophages, shed large amounts of PLM, which triggers an intense phosphotyrosine kinase-dependent signaling pathway and the secretion of TNF-α (19Jouault T. Fradin C. Trinel P.A. Bernigaud A. Poulain D. J. Infect. Dis. 1998; 178: 792-802Crossref PubMed Scopus (49) Google Scholar). The synthesis of surface glycolipids that protect from host defenses and/or disturb host cell immune functions is recognized as a pathogenic characteristic of eukaryotic protozoa of the genera Leishmania and Trypanosoma(20Schofield L. Tachado S. Immunol. Cell Biol. 1996; 74: 555-563Crossref PubMed Scopus (49) Google Scholar) and of prokaryotes of the genus Mycobacteria(21Barnes P.F. Chatterjee D. Abrams J.S. Lu S. Wang E. Yamamura M. Brennan P.J. Modlin R.L. J. Immunol. 1992; 149: 541-547PubMed Google Scholar, 22Dahl K.E. Shiratsuchi H. Hamilton B.D. Ellner J.J. Toossi Z. Infect. Immun. 1996; 64: 399-405Crossref PubMed Google Scholar, 23Yoshida A. Koide Y. Infect. Immun. 1997; 65: 1953-1955Crossref PubMed Google Scholar). In this study we analyzed PLM to obtain chemical evidence for the presence of β-1,2-oligomannosides and to assess the possible structural relationships with surface glycolipids of these other microbial pathogens. Like these glycolipids, the C. albicansPLM was metabolically labeled by [3H]mannose and [3H]inositol, and both labeling profiles were superimposed in a family of hydrophilic glycolipids with β-1,2-oligomannosidic epitopes. The physicochemical analysis of the PLM sugar moiety confirmed the presence of mannose and inositol and evidenced the absence of glucosamine. The absence of this residue is consistent with the PLM resistance to nitrous acid treatment (29Ferguson M.A.J. Fukuda M. Kobata A. Glycobiology: A Practical Approach. IRL Press, Oxford, UK1993: 349-384Google Scholar) and its unlabeling with [3H]glucosamine (unpublished data). Glucosamine linking inositol to the sugar moiety is a common feature of GPI and GPI-related glycolipids (39McConville M.J. Ferguson M.A.J. Biochem. J. 1993; 294: 305-324Crossref PubMed Scopus (798) Google Scholar) of eukaryotic cells. Its absence has only been reported to date in lipoarabinomannan, a GPI-like structure from prokaryotes of the genus Mycobacteria. Another peculiarity of PLM lies in the exclusive presence of β-1,2-linked mannose residues in its sugar moiety, which were found to be organized in linear chains with degrees of polymerization ranging from 8 to 18. Confirmation of the probable presence of a Man-1-phosphate linkage in the molecule, as deduced from NMR spectrum, will require further studies. The average mass of PLM may be estimated, from the present study, to be about 4 kDa. This mass is different from the former description of the PLM as corresponding to a C. albicans 14–18-kDa antigen in Western blotting (16Trinel P.A. Faille C. Jacquinot P.M. Cailliez J.C. Poulain D. Infect. Immun. 1992; 60: 3845-3851Crossref PubMed Google Scholar). By using more reticulated gels (7–20% acrylamide) and migration conditions favoring the progressive blockage of the molecules in the gel rather than their migration speed, we observed that the PLM relative molecular mass upon SDS-PAGE decreased to 7 kDa (data not shown). In Fig. 7 we suggest a structural model for the PLM glycan moiety, based on the first chemical evidence for the presence of β-1,2-linked oligomannosides in a glycoconjugate other than the yeast phosphopeptidomannan. Very little is known about β-1,2-mannosyltransferases of C. albicans, their activation and substrate specificity, but the presence of such linear chains of up to 18 mannose residues represent quite unusual structures (24Trinel P.A. Lepage G. Jouault T. Strecker G. Poulain D. FEBS Lett. 1997; 416: 203-206Crossref PubMed Scopus (29) Google Scholar). It has been suggested that a consequence of coating parasite surfaces with long sugar chains is the triggering of host effector mechanisms at a distance too great for efficient antimicrobial activity on the parasite. The recent demonstration for the presence of PLM at the C. albicans cell wall surface (19Jouault T. Fradin C. Trinel P.A. Bernigaud A. Poulain D. J. Infect. Dis. 1998; 178: 792-802Crossref PubMed Scopus (49) Google Scholar) suggests that these mechanisms may play a role during host-C. albicansinteraction. Moreover, β-1,2-oligomannosides have been shown to act as C. albicans adhesins for the macrophage membrane (15Fradin C. Jouault T. Mallet A. Mallet J. Camus D. Sinaÿ P. Poulain D. J. Leukocyte Biol. 1996; 60: 81-87Crossref PubMed Scopus (73) Google Scholar) and to stimulate macrophages to produce high levels of TNF-α (13Jouault T. Lepage G. Bernigaud A. Trinel P.A. Fradin C. Wieruszeski J.M. Strecker G. Poulain D. Infect. Immun. 1995; 63: 2378-2381Crossref PubMed Google Scholar, 18Jouault T. Bernigaud A. Lepage G. Trinel P. Poulain D. Immunology. 1994; 83: 268-273PubMed Google Scholar). The stimulating activity of β-1,2-oligomannosides was found to depend on the length of the mannosyl chain and maximum activity was observed for DPs of 8 or higher (13Jouault T. Lepage G. Bernigaud A. Trinel P.A. Fradin C. Wieruszeski J.M. Strecker G. Poulain D. Infect. Immun. 1995; 63: 2378-2381Crossref PubMed Google Scholar). Interestingly, these high DPs are present mainly in the C. albicans PLM but correspond to minor components among the β-1,2-oligomannosides released from the mannan of the same species (24Trinel P.A. Lepage G. Jouault T. Strecker G. Poulain D. FEBS Lett. 1997; 416: 203-206Crossref PubMed Scopus (29) Google Scholar). In conclusion, we have shown that the pathogenic yeast C. albicans synthesizes inositol-labeled glycolipids that have glycan moieties devoid of glucosamine. These C. albicansglycolipids are thus structurally more similar to lipoarabinomannans ofMycobacteria than to the glycosylinositolphospholipids of parasitic protozoa or the lipophosphoglycan of Leishmania. Recently, as well as being B cell antigens, mannose sequences of lipoarabinomannan have been implicated in the presentation to T cells by CD1b nonclassical major histocompatibility complex molecules (40Prigozy T.I. Seiling P.A. Clemens D. Stewart P.L. Behar S.M. Porcelli S.A. Brenner M.B. Modlin R.L. Kronenberg M. Immunity. 1997; 6: 187-197Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar). Whether or not this property is shared by C. albicans PLM remains to be investigated. An important PLM structural peculiarity lies in the presence of long chains of β-1,2-linked mannose residues. There is now considerable experimental evidence that these sugar residues are involved in virulence and immunomodulation and can elicit protective antibody responses. Therefore, PLMs are molecules that must be considered for a comprehensive analysis of host-C. albicans relationships. A complete elucidation of their structure and biosynthetic pathways will be necessary to provide a structural basis for understanding their immunochemical properties and some aspects of the pathogenesis of C. albicans infections. We gratefully acknowledge Dr. Margarete Borg-Von-Zepelin (University of Göttingen, Germany) for providing monoclonal antibody DF9-3. We thank Pr. Casadevall (Albert Einstein College of Medecine, Bronx, NY) for helpful improvements and correction of the manuscript and Pr. Ferguson (University of Dundee, Scotland) for constructive criticism." @default.
W2052675223 created "2016-06-24" @default.
W2052675223 creator A5012702039 @default.
W2052675223 creator A5014012945 @default.
W2052675223 creator A5018948877 @default.
W2052675223 creator A5052167711 @default.
W2052675223 creator A5055559518 @default.
W2052675223 creator A5064377376 @default.
W2052675223 creator A5067398092 @default.
W2052675223 creator A5089955573 @default.
W2052675223 date "1999-10-01" @default.
W2052675223 modified "2023-10-16" @default.
W2052675223 title "The Candida albicans Phospholipomannan Is a Family of Glycolipids Presenting Phosphoinositolmannosides with Long Linear Chains of β-1,2-Linked Mannose Residues" @default.
W2052675223 cites W1543731498 @default.
W2052675223 cites W1560324107 @default.
W2052675223 cites W1566187942 @default.
W2052675223 cites W1777180563 @default.
W2052675223 cites W1859734622 @default.
W2052675223 cites W1885188225 @default.
W2052675223 cites W1907950934 @default.
W2052675223 cites W1919230365 @default.
W2052675223 cites W1944304173 @default.
W2052675223 cites W1970467918 @default.
W2052675223 cites W1987522174 @default.
W2052675223 cites W2003604347 @default.
W2052675223 cites W2010485836 @default.
W2052675223 cites W2012877172 @default.
W2052675223 cites W2013857975 @default.
W2052675223 cites W2051405598 @default.
W2052675223 cites W2057007315 @default.
W2052675223 cites W2068377703 @default.
W2052675223 cites W2069214375 @default.
W2052675223 cites W2071482962 @default.
W2052675223 cites W2073414803 @default.
W2052675223 cites W2092477758 @default.
W2052675223 cites W2098144361 @default.
W2052675223 cites W2100285257 @default.
W2052675223 cites W2102098249 @default.
W2052675223 cites W2102993886 @default.
W2052675223 cites W2104191600 @default.
W2052675223 cites W2115681469 @default.
W2052675223 cites W2126716811 @default.
W2052675223 cites W2128128380 @default.
W2052675223 cites W2129758750 @default.
W2052675223 cites W2137507556 @default.
W2052675223 cites W2139339312 @default.
W2052675223 cites W2147969002 @default.
W2052675223 cites W2231191919 @default.
W2052675223 cites W2259986462 @default.
W2052675223 cites W2263576957 @default.
W2052675223 cites W2335592622 @default.
W2052675223 doi "https://doi.org/10.1074/jbc.274.43.30520" @default.
W2052675223 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/10521433" @default.
W2052675223 hasPublicationYear "1999" @default.
W2052675223 type Work @default.
W2052675223 sameAs 2052675223 @default.
W2052675223 citedByCount "43" @default.
W2052675223 countsByYear W20526752232012 @default.
W2052675223 countsByYear W20526752232013 @default.
W2052675223 countsByYear W20526752232014 @default.
W2052675223 countsByYear W20526752232015 @default.
W2052675223 countsByYear W20526752232017 @default.
W2052675223 countsByYear W20526752232018 @default.
W2052675223 countsByYear W20526752232023 @default.
W2052675223 crossrefType "journal-article" @default.
W2052675223 hasAuthorship W2052675223A5012702039 @default.
W2052675223 hasAuthorship W2052675223A5014012945 @default.
W2052675223 hasAuthorship W2052675223A5018948877 @default.
W2052675223 hasAuthorship W2052675223A5052167711 @default.
W2052675223 hasAuthorship W2052675223A5055559518 @default.
W2052675223 hasAuthorship W2052675223A5064377376 @default.
W2052675223 hasAuthorship W2052675223A5067398092 @default.
W2052675223 hasAuthorship W2052675223A5089955573 @default.
W2052675223 hasBestOaLocation W20526752231 @default.
W2052675223 hasConcept C185592680 @default.
W2052675223 hasConcept C22222904 @default.
W2052675223 hasConcept C2775887612 @default.
W2052675223 hasConcept C2780917455 @default.
W2052675223 hasConcept C55493867 @default.
W2052675223 hasConcept C71240020 @default.
W2052675223 hasConcept C86803240 @default.
W2052675223 hasConcept C89423630 @default.
W2052675223 hasConceptScore W2052675223C185592680 @default.
W2052675223 hasConceptScore W2052675223C22222904 @default.
W2052675223 hasConceptScore W2052675223C2775887612 @default.
W2052675223 hasConceptScore W2052675223C2780917455 @default.
W2052675223 hasConceptScore W2052675223C55493867 @default.
W2052675223 hasConceptScore W2052675223C71240020 @default.
W2052675223 hasConceptScore W2052675223C86803240 @default.
W2052675223 hasConceptScore W2052675223C89423630 @default.
W2052675223 hasIssue "43" @default.
W2052675223 hasLocation W20526752231 @default.
W2052675223 hasOpenAccess W2052675223 @default.
W2052675223 hasPrimaryLocation W20526752231 @default.
W2052675223 hasRelatedWork W1969197097 @default.
W2052675223 hasRelatedWork W1987664815 @default.
W2052675223 hasRelatedWork W1996792616 @default.
W2052675223 hasRelatedWork W2013247432 @default.