Characterization of Binding of
            <i>Candida albicans</i>
            to Small Intestinal Mucin and Its Role in Adherence to Mucosal Epithelial Cells

Repentigny, Louis de; Aumont, Francine; Bernard, Kristen A.; Belhumeur, Pierre

doi:10.1128/iai.68.6.3172-3179.2000

Cited by 106 publications

(72 citation statements)

References 64 publications

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“…Moreover, it was demonstrated that the degraded mucins were less effective in inhibiting adherence of amoebae to target epithelial cells, indicating that the mucin polymer must be intact to maintain its protective function. Similar observations have been reported for Candida albicans, where the mucin was degraded by the secreted aspartyl protease Sap2p (14). E.h. trophozoites expressing the antisense message to EhCP5 (E.h. cysteine protease 5) (15) have an impaired ability to disrupt an intact colonic mucus barrier and invade epithelial cell monolayers (16).…”

supporting

confidence: 73%

Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel

Lidell

Moncada

Chadee

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

237

182

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In order for the protozoan parasite Entamoeba histolytica (E.h.) to cause invasive intestinal and extraintestinal infection, which leads to significant morbidity and mortality, it must disrupt the protective mucus layer by a previously unknown mechanism. We hypothesized that cysteine proteases secreted from the amoeba disrupt the mucin polymeric network, thereby overcoming the protective mucus barrier. The MUC2 mucin is the major structural component of the colonic mucus gel. Heavily O-glycosylated and protease-resistant mucin domains characterize gel-forming mucins. Their N-and C-terminal cysteine-rich domains are involved in mucin polymerization, and these domains are likely to be targeted by proteases because they are less glycosylated, thereby exposing their peptide chains. By treating recombinant cysteine-rich domains of MUC2 with proteases from E.h. trophozoites, we showed that the C-terminal domain was specifically targeted at two sites by cysteine proteases, whereas the N-terminal domain was resistant to proteolysis. The major cleavage site is predicted to depolymerize the MUC2 polymers, thereby disrupting the protective mucus gel. The ability of the cysteine proteases to dissolve mucus gels was confirmed by treating mucins from a MUC2-producing cell line with amoeba proteases. These findings suggest a major role for E.h. cysteine proteases in overcoming the protective mucus barrier in the pathogenesis of invasive amoebiasis. In this report, we identify a specific cleavage mechanism used by an enteric pathogen to disrupt the polymeric nature of the mucin gel.colon ͉ parasite

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supporting

confidence: 73%

Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel

Lidell

Moncada

Chadee

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

237

182

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“…2. Sap2 is known to degrade many human proteins including molecules that protect mucosal surfaces such as mucin (36,52) and secretory immunoglobulin A (IgA) (78,184). Not only could this provide essential nitrogen for growth, but also it could enhance attachment, colonization, and penetration of host tissue by the removal of host barriers.…”

Section: Degradation Of Human Proteins and Structural Analysis Inmentioning

confidence: 99%

Candida albicansSecreted Aspartyl Proteinases in Virulence and Pathogenesis

Naglik

Challacombe

Hube

2003

Microbiol Mol Biol Rev

1,012

970

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Candida albicans is the most common fungal pathogen of humans and has developed an extensive repertoire of putative virulence mechanisms that allows successful colonization and infection of the host under suitable predisposing conditions. Extracellular proteolytic activity plays a central role in Candida pathogenicity and is produced by a family of 10 secreted aspartyl proteinases (Sap proteins). Although the consequences of proteinase secretion during human infections is not precisely known, in vitro, animal, and human studies have implicated the proteinases in C. albicans virulence in one of the following seven ways: (i) correlation between Sap production in vitro and Candida virulence, (ii) degradation of human proteins and structural analysis in determining Sap substrate specificity, (iii) association of Sap production with other virulence processes of C. albicans, (iv) Sap protein production and Sap immune responses in animal and human infections, (v) SAP gene expression during Candida infections, (vi) modulation of C. albicans virulence by aspartyl proteinase inhibitors, and (vii) the use of SAP-disrupted mutants to analyze C. albicans virulence. Sap proteins fulfill a number of specialized functions during the infective process, which include the simple role of digesting molecules for nutrient acquisition, digesting or distorting host cell membranes to facilitate adhesion and tissue invasion, and digesting cells and molecules of the host immune system to avoid or resist antimicrobial attack by the host. We have critically discussed the data relevant to each of these seven criteria, with specific emphasis on how this proteinase family could contribute to Candida virulence and pathogenesis

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“…Examples of such characteristics include the inability to grow at 45°C, the production of multiple terminal chlamydoconidia, and assimilation of xylose. C. dubliniensis appears to have greater expression than C. albicans of some characteristics generally considered to be associated with virulence, such as aspartyl protease production and possibly adhesion to buccal epithelial cells (7,8,12,44), although its ability to bind to mucin appears similar to that of C. albicans (9). C. dubliniensis also appears to more easily develop resistance to fluconazole, which is commonly used to treat oropharyngeal candidiasis (6,56,57).…”

mentioning

confidence: 99%

Comparison of the Hydrophobic Properties of Candida albicans and Candida dubliniensis

Hazen

Wu²,

Masuoka³

2001

Infect Immun

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Although Candida dubliniensis is a close genetic relative of Candida albicans, it colonizes and infects fewer sites. Nearly all instances of candidiasis caused by C. dubliniensis are restricted to the oral cavity. As cell surface hydrophobicity (CSH) influences virulence of C. albicans, CSH properties of C. dubliniensis were investigated and compared to C. albicans. Growth temperature is one factor which affects the CSH status of stationaryphase C. albicans. However, C. dubliniensis, similar to other pathogenic non-albicans species of Candida, was hydrophobic regardless of growth temperature. For all Candida species tested in this study (C. albicans, C. dubliniensis, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis), CSH status correlated with coaggregation with the anaerobic oral bacterium Fusobacterium nucleatum. Previous studies have shown that CSH status of C. albicans involves multiple surface proteins and surface protein N-glycans. The hydrophobic surface glycoprotein CAgp38 appears to be expressed by C. albicans constitutively regardless of growth temperature and medium. C. dubliniensis expresses a 38-kDa protein that cross-reacts with the anti-CAgp38 monoclonal antibody; however, expression of the protein was growth medium and growth temperature dependent. The anti-CAgp38 monoclonal antibody has been shown to inhibit adhesion of C. albicans to extracellular matrix proteins and to vascular endothelial cells. Since protein glycosylation influences the CSH status of C. albicans, we compared the cell wall mannoprotein content and composition between C. albicans and C. dubliniensis. Similar bulk compositional levels of hexose, phosphate, and protein in their N-glycans were determined. However, a component of the C. albicans N-glycan, acid-labile phosphooligomannoside, is expressed much less or negligibly by C. dubliniensis, and when present, the oligomannosides are predominantly less than five mannose residues in length. In addition, the acid-labile phosphooligomannoside profiles varied among the three strains of C. dubliniensis we tested, indicating the N-glycan of C. dubliniensis differs from C. albicans. For C. albicans, the acid-labile phosphooligomannoside influences virulence and surface fibrillar conformation, which affects exposure of hydrophobic surface proteins. Given the combined role in C. albicans of expression of specific surface hydrophobic proteins in pathogenesis and of surface protein glycosylation on exposure of the proteins, the lack of these virulence-associated CSH entities in C. dubliniensis could contribute to its limited ability to cause disseminated infections.

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Characterization of Binding of Candida albicans to Small Intestinal Mucin and Its Role in Adherence to Mucosal Epithelial Cells

Cited by 106 publications

References 64 publications

Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel

Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel

Candida albicansSecreted Aspartyl Proteinases in Virulence and Pathogenesis

Comparison of the Hydrophobic Properties of Candida albicans and Candida dubliniensis

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