Skip Navigation

Recognition of Candida albicans by Mannan-Binding Lectin In Vitro and In Vivo

  1. Joseph B. Lillegard1,2,
  2. Robert B. Sim3,
  3. Peter Thorkildson1,
  4. Marcellene A. Gates1 and
  5. Thomas R. Kozel1,2
  1. 1Department of Microbiology and Immunology, University of Nevada School of Medicine, and
  2. 2Cell and Molecular Biology Program, University of Nevada, Reno;
  3. 3Medical Research Council Immunochemistry Unit, University of Oxford, Department of Biochemistry, Oxford, United Kingdom
  1. Reprints or correspondence: Dr. Thomas R. Kozel, Dept. of Microbiology and Immunology/320, University of Nevada School of Medicine, Reno, NV 89557 (trkozel{at}med.unr.edu)
 
Next Section

Abstract

Mannan-binding lectin (MBL) is a component of the innate immune system. The goal of the present study was to evaluate binding of MBL to Candida albicans in vitro and in vivo and to assess the impact of MBL treatment on host resistance. The results showed a variable and often discontinuous pattern of binding to individual yeast cells. MBL bound to cells grown at 37°C but not to cells grown at 23°C. The putative MBL ligand was constitutively present on yeast cells grown at 23°C, but the ligand was masked on such cells, such that MBL could not bind. C. albicans yeasts and hyphae in infected tissue bound MBL. Finally, parenteral administration of MBL increased resistance of mice to hematogenously disseminated candidiasis. These results suggest that MBL is an important component of innate resistance to candidiasis and that MBL therapy may be a means to prevent disseminated candidiasis in high-risk patients

Candida species are a leading cause of nosocomial bloodstream infection in US hospitals [1]. Even with antifungal therapy, the attributable mortality of nosocomial candidemia is 40%–50% [2]. Innate resistance to disseminated candidiasis is relatively high, and disseminated disease is characteristically associated with well-described risk factors that include gastrointestinal or cardiac surgery, prolonged stay in an intensive care unit, burns, use of central venous catheters, use of broad-spectrum antibiotics, use of parenteral nutrition, and immunocompromise due to cancer, neutropenia, or corticosteroid use [3, 4]

Mannan-binding lectin (MBL) is a key component of the innate immune system, and MBL deficiencies have been associated with a wide spectrum of infectious diseases, including fungal infections [5–8]. Babula et al. found reduced MBL levels and an increased occurrence of the codon 54 MBL polymorphism in women with recurrent vulvovaginal candidiasis, suggesting a role for MBL in host resistance [8]. MBL has the ability to distinguish between self and nonself by recognizing certain patterns of carbohydrate structures. The molecular basis for recognition by MBL lies in binding to sugars that contain vicinal equatorial hydroxyl groups, such as those found at the 3-OH and 4-OH positions of mannose, N-acetylglucosamine, and fucose [9, 10]

Candida species are coated with mannoproteins that display mannan in a variety of linkages. However, growth conditions may dramatically influence expression of mannoproteins at the cell surface. For example, hyphae and yeast cells grown at room temperature have a hydrophobic surface, whereas yeast cells grown at 37°C are hydrophilic [11–14]. Many of the mannose residues found in Candida mannan present hydroxyl groups in the 3-OH and 4-OH positions needed for MBL recognition [15–17]. As a consequence, Candida mannan is a likely target for MBL binding. Two previous studies used flow cytometry to demonstrate that MBL does, indeed, bind to C. albicans yeast cells [18, 19]. However, the patterns of MBL binding to individual yeast cells and the influence of yeast growth conditions on MBL binding are not known. Moreover, demonstration of a definitive role for MBL in host resistance to candidiasis has been elusive [20]. The goals of our study were (1) to determine the patterns of MBL binding to individual cells, (2) to assess the influence of growth conditions on expression of a putative ligand that is recognized by MBL, (3) to assess the extent to which C. albicans expresses the MBL ligand in vivo, and (4) to determine whether parenteral administration of MBL can alter the course of hematogenously disseminated candidiasis in a murine model

Previous SectionNext Section

Materials and Methods

MBL purificationMBL was isolated from human plasma by differential precipitation with PEG 3350 and affinity chromatography on mannan agarose and maltose agarose [21]. Contaminating immunoglobulins were removed by immunoaffinity chromatography with goat anti–human immunoglobulin (Southern Biotechnology). MBL was dissociated from MBL-associated protease by dialysis against 5 mmol/L sodium acetate (pH 5.0), followed by molecular sieve chromatography on Superdex 200 (Pharmacia) [21]. The isolated protein was identified as MBL by N-terminal sequencing (data not shown). Evaluation of the product by SDS-PAGE under reducing conditions showed that >97% of the protein was a single band of 35 kDa, a molecular size that is consistent with MBL [21]. The majority of the contaminating protein was of a molecular size that is consistent with a dimer of MBL

C. albicans. Two strains of C. albicans serotype A (ATCC 36801 and ATCC 28367), C. albicans serotype B (ATCC 36803), C. glabrata (ATCC 2001), C. krusei (ATCC 14243), C. guilliermondii (ATCC 6260), and Saccharomyces cerevisiae (ATCC 26786) were used. Yeast cells were grown at 23°C to produce cells with hydrophobic surfaces or at 37°C to produce cells with hydrophilic surfaces, as described elsewhere [11] with the exception that a synthetic medium [22] was used in place of Sabouraud dextrose broth. The hydrophobic or hydrophilic nature of the cell surface was confirmed by a polystyrene microsphere assay [12]

Temperature and pH shifts were used to evaluate the effects of a change in the growth environment on MBL binding. These studies used a synthetic medium [22], as adapted by Buffo et al. [23]. The temperature shift from 23°C to 37°C was accompanied by a pH shift from 6.8 to 4.5, to prevent formation of mycelia [23]. A temperature shift from 23°C to 37°C at pH 6.8 was used to induce hyphal growth [23]. All cell preparations were fixed overnight at 4°C with 1% formaldehyde

Immunofluorescence evaluation of MBL binding to C. albicans. Fixed cells were washed with VB2+ (sodium Veronal [5 mmol/L]–buffered saline [142 mmol/L], pH 7.5, containing 0.15 mmol/L CaCl2 and 1 mmol/L MgCl2), and ∼2×106 cells were incubated for 30 min at 37°C with 50 μL of MBL (4 μg/mL) in VB2+. The cells were washed with VB2+, incubated for 15 min at 37°C with 50 μL of biotinylated murine anti–human MBL monoclonal antibody (MAb) (2 μg/mL; Statens Seruminstitut), washed with VB2+, incubated for 15 min at 37°C with 50 μL of streptavidin–fluorescein isothiocyanate (110 μg/mL; Pierce), washed 3 times with VB2+, and resuspended in Vectashield (Vector Laboratories)

Binding of human MBL to C. albicans in infected tissue was also evaluated. Female BALB/c mice were infected intravenously with 7.5×105 cells of C. albicans serotype A. Three days later, various organs were collected, fixed in 10% buffered formalin, dehydrated in ethanol and xylene, embedded in paraffin, and cut into 6–8-μm sections. The sections were deparaffinized, hydrated with water, and washed with VB containing 40 mmol/L EDTA, to dissociate murine MBL that might be adherent to C. albicans in tissue. The sections were incubated for 30 min at 37°C with purified human MBL (4 μg/mL VB2+), and bound MBL was stained using biotinylated mouse anti–human MBL MAb

Immunofluorescence analysis was performed with a Nikon Eclipse E800 microscope fitted with a Nikon C1 confocal microscopy system. Stereoscopic images were constructed from a Z stack of images acquired at 0.35-μm increments; a 3-dimensional effect was rendered by rotating each image stack 11° along its vertical axis. Tissue sections were also examined for immunofluorescent and hematoxylin-eosin staining by light and epifluorescence microscopy. Digital deconvolution of selected confocal images was performed using AutoDeblur and AutoVisualization (version 9.2; AutoQuant)

Flow cytometryYeast cells to be examined for MBL binding were treated with MBL and immunostained for MBL as described above; at least 2.5×104 cells were analyzed for each group. A FL-1 525-band pass filter was used for green fluorescence, which was collected with log amplification. Gain settings used to generate the various figures were optimized for each experiment and were not held constant throughout the study

Competitive inhibition assay for binding of MBL to purified mannanMannan was isolated from S. cerevisiae grown at 37°C on yeast extract peptone dextrose broth. Mannan was also isolated from C. albicans serotype A grown for 60 h on synthetic medium [22] at pH 6.8 and from similar 60-h cultures that were diluted into fresh, prewarmed (37°C) medium at pH 4.5 and incubated for an additional 80 min. Mannan was extracted by heating the cells in water for 4 h at 121°C [24]. Water-soluble mannan was precipitated with Fehling solution [24–26], solubilized by incubation with Amberlite IR-120 resin (Aldrich), dialyzed against water, and recovered by lyophilization

For the inhibition assay, wells of microtiter plates (Immulon 1B; Thermo Labsystems) were coated overnight with S. cerevisiae mannan (10 μg/mL in 50 mmol/L NaHCO3; pH 9.5). The wells were washed with blocking solution (Tris-buffered saline containing 0.75 mmol/L Ca2+ and 0.05% Tween 20) and incubated for an additional 2 h with blocking solution. All subsequent steps were performed in blocking solution. Serial dilutions of mannan from C. albicans grown at 23°C or temperature shifted to 37°C were mixed with a fixed concentration of MBL (15 pg/μL), added to the wells coated with S. cerevisiae mannan, and incubated for 90 min. Binding of MBL to the wells was assessed by incubation for 90 min with biotinylated anti–human MBL MAb (10 μg/mL), followed by incubation with neutravidin–horseradish peroxidase (50 μg/mL) and substrate (3,3′,5,5′-tetramethylbenzidine; Kirkegaard and Perry)

Modification of C. albicans.C. albicans serotype A cells (ATCC 36801) were grown on synthetic medium for production of hydrophobic cells (23°C; pH 4.5). The yeast cells were fixed with 1% formaldehyde. The cells were suspended in Tris buffer (50 mmol/L; pH 7.5) and passed through a FACS Vantage fluorescence-activated cell sorter (Becton Dickinson). The passaged cells were incubated with MBL as described above and immunostained for MBL binding. C. albicans cells grown as described above were also treated with 10 mmol/L HCl at 100°C, to remove the acid-labile portion of mannan [27], and the ability of the treated cells to bind MBL was assessed

Treatment of mice with purified MBLMice were treated by intravenous administration of 15 μg of human MBL in 200 μL of PBS or were sham treated with PBS alone. The mice were challenged 1 h later by intravenous injection of various doses of C. albicans serotype A (ATCC 36801) that had been grown on synthetic medium for production of hydrophilic cells (37°C). Mice were weighed daily and observed for 30 days for death or signs of significant morbidity. Mice having a 20% weight loss were considered to be moribund and were killed

Statistical analysisSurvival analysis was performed by use of Kaplan-Meier curves, with tests of significance by the log-rank test

Previous SectionNext Section

Results

Binding of MBL to C. albicansyeast cells and hyphae in vitroAn initial experiment utilized confocal microscopy to assess the sites and patterns of binding of MBL to C. albicans. Yeast cells (ATCC 36801) were grown at 37°C, fixed, incubated with purified MBL, and stained for MBL binding. The results (figure 1) showed a striking diversity in binding patterns. In some cases, binding was diffuse and continuous over the cell surface; more often, the distribution was punctate or patchy. Some cells bound little or no MBL. In many cases, MBL showed more binding to buds than to mother cells. Identical results were found with a second serotype A strain (ATCC 3153A; data not shown). A similar diversity in binding was observed with hyphae. MBL binding to hyphae ranged from continuous to patchy to punctate to areas with little or no binding. Binding of MBL to C. albicans yeast cells was inhibited by treatment of the MBL with 40 mmol/L EDTA or with 90 mmol/L mannose or N-acetylglucosamine but not with 90 mmol/L galactose (data not shown)

Figure 1
View larger version:
Figure 1

Diversity in patterns of mannan-binding lectin (MBL) binding to Candida albicans serotype A. Yeast cells were grown under conditions that produce hydrophilic cell surfaces (37°C; upper panels). A temperature shift from 23°C to 37°C at pH 6.8 was used to induce hyphal growth (lower panels). Yeast cells or hyphae were incubated with human MBL, and binding of MBL was identified by use of an anti-MBL monoclonal antibody. In the case of hyphae, a Z stack of images was collected through the hyphal mass. The right image is an 11° rotation of the left image, allowing for stereoscopic viewing of MBL binding

Yeast cells of various Candida species display mannans with different antigenic factors at the cell surfaces [28–30]. Consequently, we used confocal microscopy and flow cytometry to assess variability between different species in binding of MBL. The results (figure 2) showed the same cell-to-cell variability in binding patterns found with C. albicans (figure 1). However, quantitative assessment by flow cytometry showed a considerable range in the amount of MBL bound per cell and a substantial difference between cells of the various species in mean fluorescence intensity (C. glabrata > C. krusei > C. albicans serotype A [ATCC 36801] > C. albicans serotype B ≈ C. guilliermondii ≈ S. cerevisiae)

Figure 2
View larger version:
Figure 2

Binding of mannan-binding lectin (MBL) to yeast cells of various Candida species and Saccharomyces cerevisiae. Yeast cells were grown under conditions that produce hydrophilic cell surfaces (37°C). Yeast cells were incubated with human MBL, and binding of MBL was identified by use of an anti-MBL monoclonal antibody. Upper panels Spatial localization of MBL deposition by confocal microscopy. Lower panels Quantitative assessment of MBL binding by flow cytometry. MFI, mean fluorescence intensity

The candidal cell surface is dramatically influenced by the conditions under which the cells are grown [11]. Consequently, we evaluated binding of MBL to yeast cells that had been grown for 10 h or 60 h at 23°C (hydrophobic surface) or 37°C (hydrophilic surface). The results (figure 3) showed the range of binding patterns noted above for cells grown at 37°C. This range of binding was evident by both confocal microscopy and flow cytometry. In contrast, there was little or no binding of MBL to cells grown at 23°C

Figure 3
View larger version:
Figure 3

Effect of culture temperature and time on binding of mannan-binding lectin (MBL) to Candida albicans serotype A. Yeast cells were grown under the indicated conditions and incubated with human MBL, and binding of MBL was identified by use of an anti-MBL monoclonal antibody. A Yeast cells grown for 10 or 60 h at 37°C. B Yeast cells grown for 10 or 60 h at 23°C. C Analysis by flow cytometry of MBL binding to yeast cells that were grown for 10 h at 23°C or 37°C

A shift in incubation temperature from room temperature to 37°C is accompanied by a shift from a hydrophobic to a hydrophilic cell surface. An experiment was performed to assess the effect of such a temperature shift on the ability of yeast cells to bind MBL. Yeast cells were cultured for 60 h at 23°C in synthetic medium at pH 6.8. The cells were then diluted into prewarmed medium (37°C) at pH 4.5, and samples were taken at various time intervals over 60 h. The shift in pH was done to prevent hyphae formation [23]. The results (figure 4) showed abundant binding at the earliest sample time of 20 min. A notable feature of cells harvested after 20 min versus those harvested after 60 h (figure 1) was a more uniform distribution of MBL on the yeast cells that was evident by both confocal microscopy and flow cytometry. The patterns of MBL binding became more variable with increasing time (data not shown). The rapid change in surface expression of the putative MBL ligand was not due to the pH shift, because cells grown at 23°C, pH 6.8, and shifted to 23°C, pH 4.5, showed no increase in MBL binding (data not shown)

Figure 4
View larger version:
Figure 4

Effect of temperature and pH shift on binding of mannan-binding lectin (MBL) to Candida albicans. Yeast cells were cultured at 23°C for 60 h on synthetic medium at pH 6.8 (time 0). The cells were then diluted 1:10 in prewarmed (37°C) medium at pH 4.5 and cultured for an additional 20 min. The cells were incubated with MBL and immunostained for MBL binding, and MBL binding was assessed by confocal microscopy (A) and flow cytometry (B)

There are 2 potential mechanisms for the rapid temperature-dependent shift in expression or availability of the ligand that is recognized by MBL. First, the epitope could be rapidly produced de novo. Alternatively, the MBL ligand could be constitutively present on all cells but be masked in cells that fail to bind MBL. In an effort to address this question, we isolated mannan from yeast cells that failed to bind MBL (60 h at 23°C; pH 6.8) and from yeast cells that bound MBL well (yeast cells grown for 60 h at 23°C, pH 6.8, and then temperature and pH shifted for 80 min at 37°C, pH 4.5). The mannan preparations were then compared in a competitive inhibition assay that examined the ability of either mannan to block binding of MBL to S. cerevisiae mannan. The results (figure 5A) showed no difference between the 2 mannan preparations

Figure 5
View larger version:
Figure 5

A mannan-binding lectin (MBL)–binding ligand constitutively present on yeast cells that do (37°C) or do not (23°C) bind MBL. A Competitive inhibition assay in which mannan was isolated from cells that either were grown at 23°C or were grown at 23°C and then temperature shifted to 37°C for 80 min and used in variable amounts as inhibitors for binding of a constant amount of MBL (15 pg/μL) to microtiter plates coated with Saccharomyces cerevisiae mannan. MBL binding was determined by use of a monoclonal antibody specific for human MBL. The results are expressed as the extent of inhibition in the presence of various amounts of mannan vs. MBL alone. B Unmasking of a putative MBL ligand on cells grown at 23°C. MBL binding was assessed on untreated yeast cells, yeast cells that had been treated with 10 mmol/L HCl, or yeast cells that had been passed through a fluorescence-activated cell sorter

Two experiments were performed to “unmask” the apparently occluded ligand on cells that bind MBL poorly. First, whole yeast cells that failed to bind MBL (23°C) were treated with 10 mmol/L HCl, a procedure that removes the acid-labile portion of the phosphomannan protein complex [31–33]. The results (figure 5B) showed an increase in MBL binding after treatment with 10 mmol/L HCl

An alternative approach to unmasking was based on a serendipitous experiment in which we attempted to sort unsynchronized, propidium iodide–stained yeast cells in an effort to examine the role of cell cycle in MBL binding. Instead of finding cell populations that showed different MBL binding activities, we found that all sorted yeast cells exhibited a dramatic increase in the availability of the MBL ligand (data not shown). On the basis of this unexpected result, we prepared yeast cells that showed no binding of MBL (23°C) and passed these untreated cells through the FACS. The results (figure 5B) showed that the cells bound no MBL before passage through the FACS. These same cells showed strong, uniformly distributed binding after sorting

Binding of MBL to tissue-localized C. albicansand enhancement of host resistance by treatment with MBLGiven the variability in expression of MBL in C. albicans grown in vitro, an experiment was performed to assess expression of the MBL ligand in vivo. Mice were infected with C. albicans and tissues were harvested 3 days after infection. Tissue sections were prepared and incubated with human MBL, and MBL binding was assessed. The results (figure 6) showed abundant MBL binding to yeast and hyphal forms in murine kidney. The binding patterns reflected the variability in MBL binding found with hyphae produced in vitro (figure 1). Similar results were found with infected spleen and liver (data not shown)

Figure 6
View larger version:
Figure 6

Mannan-binding lectin (MBL) binding to Candida albicans in infected murine kidney. Kidney tissue was collected from C. albicans–infected mice. Top 4 panels Sections were prepared, incubated with human MBL, immunostained for MBL binding, and then stained with hematoxylin-eosin. Sections were examined by light and epifluorescence microscopy. Bottom 2 panels Slides were prepared as described for the top panels, with the exception that they were not stained with hematoxylin-eosin. Optical sections were acquired through the tissue by confocal microscopy and are shown as a stereoscopic pair

A final experiment was performed to assess the effect of MBL treatment on survival after an intravenous challenge with C. albicans. Mice were treated intravenously with 15 μg of MBL. In an initial experiment, mice were challenged 1 h later with 4 ×105 or 6×105 yeast cells. In a second experiment, mice were challenged with 106 yeast cells. The results (figure 7) showed significant prolongation of survival for mice challenged with 6×105 (P=.014) or 106 (P=.001) cells

Figure 7
View larger version:
Figure 7

Effect of parenteral administration of human mannan-binding lectin (MBL) on resistance of mice to hematogenously disseminated candidiasis. Mice were injected intravenously with 15 μg of purified human MBL in PBS or with PBS alone and challenged 1 h later via the intravenous route with Candida albicans yeast cells that had been grown at 37°C. In experiment 1, mice were challenged with 4×105 (7 mice/group; left panel) or 6×105 (6 mice in MBL-treated group, 8 mice in sham-treated control group; center panel) cells. In experiment 2, mice were challenged with 106 yeast cells (8 mice in MBL-treated group, 10 mice in sham-treated control group; right panel)

Previous SectionNext Section

Discussion

The first description of what was eventually found to be MBL deficiency was a report of an infant with severe recurrent infections [34]. The deficiency was initially characterized as the lack of an inherited plasma factor necessary for optimal phagocytosis of baker’s yeast. The plasma factor was subsequently found to be MBL [35]. Like that of S. cerevisiae the cell wall of C. albicans has a high mannan content, and the linkages of mannose within Candida mannan are appropriate for recognition by MBL. As a consequence, it is not surprising that C. albicans yeast cells bind MBL [18, 19]. Our studies confirm binding of MBL to C. albicans and extend this observation to include hyphae and yeast and hyphal elements found in tissue. A novel aspect of our results is the extraordinary variability in binding to individual cells and the extent to which culture conditions influence expression of the MBL ligand

The specific ligand or epitope recognized by MBL is not known. C. albicans mannan displays a complex array of epitopes or factors, some of which are shared by different Candida species and others of which are unique to 1 or more species [28–30]. Our results differ from these studies of antigenic factors, because the described antigenic factors are displayed on the surface of yeast cells grown at room temperature [30, 36]. Since there is little or no binding of MBL to yeast cells grown at room temperature, the MBL ligand would appear not to be a component recognized by the various factor sera

Our results showing variable patterns of binding to yeast cells are consistent with studies of binding of antimannan MAbs to C. albicans. Epitopes recognized by some MAbs are diffusely and continuously expressed on the surface of yeast cells—for example, MAb C6 [37], MAb 24 [38], and MAb CA1 [39]. In contrast, epitopes recognized by other MAbs are expressed as discontinuous punctate or patchy patterns—for example, MAb B6.1 [40] and MAb AF1 [39]. Expression of the ligand recognized by MBL is most similar to expression of epitopes recognized by MAbs B6.1 and AF1

Our culture conditions were chosen to replicate conditions that lead to production of hydrophobic (23°C) or hydrophilic (37°C) cell surfaces [11, 13]. Cells grown under conditions that produce hydrophobic surfaces (23°C) failed to bind MBL, whereas cells grown under conditions that produce hydrophilic surfaces (37°C) bound MBL. This raises a question as to whether there is a causal relationship between a hydrophobic or hydrophilic surface and binding or a failure to bind MBL. Several aspects of the results suggest that this is not the case. First, hyphae have hydrophobic surfaces [12, 14]; we found that MBL bound to hyphae produced in vitro and in vivo. Second, buds are more hydrophobic than are the mother cells [12, 14]; we found abundant binding of MBL to yeast buds. Finally, cell surface hydrophilicity is believed to occur when hydrophilic proteins mask the presence of a hydrophobic component on the surface of hydrophilic cells [13, 41]. Our studies of unmasking of the MBL ligand show the reverse effect

There are at least 2 explanations for the influence of culture conditions on surface expression of the MBL ligand. First, expression of the ligand could depend on variable expression of a mannoprotein that does or does not display the ligand that is dependent on the culture conditions. Alternatively, the ligand could be constitutively present but be masked on cells that fail to bind MBL. Several lines of evidence support the masking model. First, mannan isolated from cells that do or do not bind MBL were similar in their ability to competitively inhibit binding of MBL to S. cerevisiae mannan (figure 5A). Second, the speed with which cells acquire the ability to bind MBL after a temperature shift (⩽20 min) likely precludes de novo synthesis as an explanation. Finally, treatment of cells that do not bind MBL with 10 mmol/L HCl or passage of cells through a FACS converted the fixed cells to cells that bound MBL, indicating that the ligand was present in cells that did not bind MBL. The specific elements of the passage of cells through a FACS that might unmask the ligand are not known but include exposure to the laser, charging of the cells, or shear forces

Finally, in our studies, we found that C. albicans cells and hyphae in tissue express surface MBL and that parenteral administration of MBL significantly increases host resistance to hematogenously disseminated candidiasis. The mechanism by which MBL treatment enhances host resistance will require further study. Disseminated candidiasis often occurs in patients whose risk factors are identifiable before development of infection. Vaccination of such identifiable high-risk patients has been suggested as a means to prevent the onset of disseminated candidiasis [42]. Our results suggest an alternative means to prevent infection in this set of patients. To this end, MBL replacement therapy has been suggested for patients with MBL deficiency [43, 44]. It is possible that such treatment may also prevent dissemination of infection in MBL-normal individuals

Previous SectionNext Section

Footnotes

  • ↵Presented in part: 103rd General Meeting of the American Society for Microbiology, 18–22 May 2003 (abstract F-109)

    Potential conflicts of interest: none reported

    Financial support: National Institutes of Health (grants P01 AI 37194 and R01 AI 44786 to T.R.K.); Burroughs Wellcome Fund (Wellcome Research Travel Grant)

  • Received October 13, 2005.
  • Accepted January 13, 2006.
Previous Section
 

References

  1. ↵
    1. Edmond MB,
    2. Wallace SE,
    3. McClish DK,
    4. Pfaller MA,
    5. Jones RN
    . Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis 1999;29:239-44.
    MedlineWeb of Science
  2. ↵
    1. Gudlaugsson O,
    2. Gillespie S,
    3. Lee K,
    4. et al
    . Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 2003;37:1172-7.
    Abstract/FREE Full Text
  3. ↵
    1. Mandell GL,
    2. Bennett JE
    1. Edwards JE Jr.
    . Candida species. In: Mandell GL, Bennett JE, editors. Principles and practice of infectious diseases. 5th ed. Philadelphia: Churchill Livingstone; 2000. p. 2656-74.
  4. ↵
    1. Spellberg BJ,
    2. Edwards JE Jr.
    . The pathophysiology and treatment of Candida sepsis. Curr Infect Dis Rep 2002;4:387-99.
    Medline
  5. ↵
    1. Crosdale DJ,
    2. Poulton KV,
    3. Ollier WE,
    4. Thomson W,
    5. Denning DW
    . Mannose-binding lectin gene polymorphisms as a susceptibility factor for chronic necrotizing pulmonary aspergillosis. J Infect Dis 2001;184:653-6.
    Abstract/FREE Full Text
  6. ↵
    1. Garred P,
    2. Madsen HO,
    3. Hofmann B,
    4. Svejgaard A
    . Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency. Lancet 1995;346:941-3.
    CrossRefMedlineWeb of Science
  7. ↵
    1. Summerfield JA,
    2. Ryder S,
    3. Sumiya M,
    4. et al
    . Mannose binding protein gene mutations associated with unusual and severe infections in adults. Lancet 1995;345:886-9.
    CrossRefMedlineWeb of Science
  8. ↵
    1. Babula O,
    2. Lazdane G,
    3. Kroica J,
    4. Ledger WJ,
    5. Witkin SS
    . Relation between recurrent vulvovaginal candidiasis, vaginal concentrations of mannose-binding lectin, and a mannose-binding lectin gene polymorphism in Latvian women. Clin Infect Dis 2003;37:733-7.
    Abstract/FREE Full Text
  9. ↵
    1. Lee RT,
    2. Ichikawa Y,
    3. Fay M,
    4. Drickamer K,
    5. Shao MC
    . Ligand-binding characteristics of rat serum-type mannose-binding protein (MBP-A): homology of binding site architecture with mammalian and chicken hepatic lectins. J Biol Chem 1991;266:4810-5.
    Abstract/FREE Full Text
  10. ↵
    1. Weiss WI,
    2. Kahn R,
    3. Fourme R,
    4. Drickamer K,
    5. Hendrickson WA
    . Structure of the calcium-dependent lectin domain from a rat mannose-binding protein determined by MAD phasing. Science 1991;254:1608-15.
    Abstract/FREE Full Text
  11. ↵
    1. Hazen BW,
    2. Hazen KC
    . Dynamic expression of cell surface hydrophobicity during initial yeast cell growth and before germ tube formation of Candida albicans. Infect Immun 1988;56:2521-5.
    Abstract/FREE Full Text
  12. ↵
    1. Hazen KC,
    2. Hazen BW
    . A polystyrene microsphere assay for detecting cell surface hydrophobicity variations within Candida albicans populations. J Microbiol Methods 1987;6:289-99.
    CrossRefWeb of Science
  13. ↵
    1. Hazen KC,
    2. Hazen BW
    . Hydrophobic surface protein masking by the opportunistic fungal pathogen Candida albicans. Infect Immun 1992;60:1499-508.
    Abstract/FREE Full Text
  14. ↵
    1. Lopez-Ribot JL,
    2. Casanova M,
    3. Martinez JP,
    4. Sentandreu R
    . Characterization of cell wall proteins of yeast and hydrophobic mycelial cells of Candida albicans. Infect Immun 1991;59:2324-32.
    Abstract/FREE Full Text
  15. ↵
    1. Kobayashi H,
    2. Komido M,
    3. Watanabe M,
    4. et al
    . Structure of cell wall mannan of Candida kefyr IFO 0586. Infect Immun 1994;62:4425-31.
    Abstract/FREE Full Text
  16. ↵
    1. Nakajima T,
    2. Ballou CE
    . Characterization of the carbohydrate fragments obtained from Saccharomyces cerevisiae mannan by alkaline degradation. J Biol Chem 1974;249:7679-84.
    Abstract/FREE Full Text
  17. ↵
    1. Shibata N,
    2. Fukasawa S,
    3. Kobayashi H,
    4. et al
    . Structural analysis of phospho-D-mannan-protein complexes isolated from yeast and mold form cells of Candida albicans NIH A-207 serotype A strain. Carbohydr Res 1989;187:239-53.
    CrossRefMedlineWeb of Science
  18. ↵
    1. Neth O,
    2. Jack DL,
    3. Dodds AW,
    4. Holzel H,
    5. Klein NJ
    . Mannose-binding lectin binds to a range of clinically relevant microorganisms and promotes complement deposition. Infect Immun 2000;68:688-93.
    Abstract/FREE Full Text
  19. ↵
    1. Ip WK,
    2. Lau YL
    . Role of mannose-binding lectin in the innate defense against Candida albicans: enhancement of complement activation, but lack of opsonic function, in phagocytosis by human dendritic cells. J Infect Dis 2004;190:632-40.
    Abstract/FREE Full Text
  20. ↵
    1. Lee SJ,
    2. Gonzalez-Aseguinolaza G,
    3. Nussenzweig MC
    . Disseminated candidiasis and hepatic malarial infection in mannose-binding-lectin-A-deficient mice. Mol Cell Biol 2002;22:8199-203.
    Abstract/FREE Full Text
  21. ↵
    1. Tan SM,
    2. Chung MCM,
    3. Kon OL,
    4. Thiel S,
    5. Lee SH
    . Improvements on the purification of mannan-binding lectin and demonstration of its Ca2+-independent association with a C1s-like serine protease. Biochem J 1996;319:329-32.
    Medline
  22. ↵
    1. Lee KL,
    2. Buckley HR,
    3. Campbell CC
    . An amino acid liquid synthetic medium for the development of mycellial and yeast forms of Candida albicans. Sabouraudia 1975;13:148-53.
    MedlineWeb of Science
  23. ↵
    1. Buffo J,
    2. Herman MA,
    3. Soll DR
    . A characterization of pH-regulated dimorphism in Candida albicans. Mycopathologia 1984;85:21-30.
    CrossRefMedline
  24. ↵
    1. Peat S,
    2. Whelan WJ,
    3. Edwards TE
    . Polysaccharides of baker’s yeast. IV: Mannan. J Chem Soc 1961;1:29-34.
  25. ↵
    1. Haworth WN,
    2. Heath RL,
    3. Peat S
    . The constitution of yeast mannan. J Chem Soc 1941;833:42.
  26. ↵
    1. Jones JKN,
    2. Stoodley RJ
    . Fractionation using copper complexes. Meth Carb Chem 1965;5:36-8.
  27. ↵
    1. Kanbe T,
    2. Cutler JE
    . Minimum chemical requirements for adhesin activity of the acid-stable part of Candida albicans cell wall phosphomannoprotein complex. Infect Immun 1998;66:5812-8.
    Abstract/FREE Full Text
  28. ↵
    1. Shinoda T,
    2. Kaufman L,
    3. Padhye AA
    . Comparative evaluation of the Iatron serological Candida Check kit and the API 20C kit for identification of medically important Candida species. J Clin Microbiol 1981;13:513-8.
    Abstract/FREE Full Text
  29. ↵
    1. Tsuchiya T,
    2. Fukazawa Y,
    3. Kawakita S
    . A method for the rapid identification of the genus Candida. Mycopathol Mycol Appl 1959;10:191-206.
    CrossRefMedline
  30. ↵
    1. Fukazawa Y,
    2. Shinoda T,
    3. Tsuchiya T
    . Response and specificity of antibodies for Candida albicans. J Bacteriol 1968;95:754-63.
    Abstract/FREE Full Text
  31. ↵
    1. Kobayashi H,
    2. Shibata N,
    3. Nakada M,
    4. et al
    . Structural study of cell wall phosphomannan of Candida albicans NIH B-792 (serotype B) strain, with special reference to 1H and 13C NMR analyses of acid-labile oligomannosyl residues. Arch Biochem Biophys 1990;278:195-204.
    CrossRefMedlineWeb of Science
  32. ↵
    1. Kobayashi H,
    2. Shibata N,
    3. Yonezu T,
    4. Suzuki S
    . Structural study of phosphomannan-protein complex of Citeromyces matritensis containing beta-1,2 linkage: application of partial acid degradation and acetolysis techniques under mild conditions. Arch Biochem Biophys 1987;256:381-96.
    CrossRefMedlineWeb of Science
  33. ↵
    1. Shibata N,
    2. Kobayashi H,
    3. Tojo M,
    4. Suzuki S
    . Characterization of phosphomannan-protein complexes isolated from viable cells of yeast and mycelial forms of Candida albicans NIH B-792 strain by the action of Zymolyase-100T. Arch Biochem Biophys 1986;251:697-708.
    CrossRefMedlineWeb of Science
  34. ↵
    1. Miller ME,
    2. Seals J,
    3. Kaye R,
    4. Levitsky LC
    . A familial, plasma associated defect of phagocytosis: a new cause of recurrent bacterial infections. Lancet 1968;ii:60-3.
    CrossRef
  35. ↵
    1. Super M,
    2. Thiel S,
    3. Lu J,
    4. Levinsky RJ,
    5. Turner MW
    . Association of low levels of mannan-binding protein with a common defect of opsonisation. Lancet 1989;2:1236-9.
    MedlineWeb of Science
  36. ↵
    Candida Check Instruction Manual. Tokyo: Iatron Laboratories;
  37. ↵
    1. Brawner DL,
    2. Cutler JE
    . Variability in expression of cell surface antigens of Candida albicans during morphogenesis. Infect Immun 1986;51:337-43.
    Abstract/FREE Full Text
  38. ↵
    1. Chaffin WL,
    2. Skudlarek J,
    3. Morrow JD
    . Variable expression of a surface determinant during proliferation of Candida albicans. Infect Immun 1988;56:302-9.
    Abstract/FREE Full Text
  39. ↵
    1. Trinel PA,
    2. Cantelli C,
    3. Bernigaud A,
    4. Jouault T,
    5. Poulain D
    . Evidence for different mannosylation processes involved in the association of β-1,2-linked oligomannosidic epitopes in Candida albicans mannan and phospholipomannan. Microbiology 1996;142:2263-70.
    Abstract/FREE Full Text
  40. ↵
    1. Han Y,
    2. Kanbe T,
    3. Cherniak R,
    4. Cutler JE
    . Biochemical characterization of Candida albicans epitopes that can elicit protective and non-protective antibodies. Infect Immun 1997;65:4100-7.
    Abstract/FREE Full Text
  41. ↵
    1. Hazen KC,
    2. Lay JG,
    3. Hazen BW,
    4. Fu RC,
    5. Murthy S
    . Partial biochemical characterization of cell surface hydrophobicity and hydrophilicity of Candida albicans. Infect Immun 1990;58:3469-76.
    Abstract/FREE Full Text
  42. ↵
    1. Ibrahim AS,
    2. Spellberg BJ,
    3. Avenissian V,
    4. Fu Y,
    5. Filler SG
    . Vaccination with recombinant N-terminal domain of ALS1p improves survival during murine disseminated candidiasis by enhancing cell-mediated, not humoral, immunity. Infect Immun 2005;73:999-1005.
    Abstract/FREE Full Text
  43. ↵
    1. Summerfield JA
    . Clinical potential of mannose-binding lectin-replacement therapy. Biochem Soc Trans 2003;31:770-3.
    CrossRefMedlineWeb of Science
  44. ↵
    1. Jensenius JC,
    2. Jensen RH,
    3. McGwire K,
    4. Larsen JL,
    5. Thiel S
    . Recombinant mannan-binding lectin (MBL) for therapy. Biochem Soc Trans 2003;31:763-7.
    CrossRefMedlineWeb of Science
| Table of Contents

This Article

  1. J Infect Dis. (2006) 193 (11): 1589-1597. doi: 10.1086/503804
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 205 (5)
  1. Journal of Infectious Diseases
  1. Alert me to new issues

Most