Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2009 Dec 30.
Published in final edited form as: Vaccine. 2008 Dec 30;26(Suppl 8):I108–I112. doi: 10.1016/j.vaccine.2008.11.056

The iC3b receptor of Candida albicans and its Roles in Pathogenesis

Margaret K Hostetter 1
PMCID: PMC2768074  NIHMSID: NIHMS89799  PMID: 19388174

Abstract

On the basis of biochemical and immunologic studies, a receptor for iC3b with some activities reminiscent of the integrins CD11b and CD11c was defined on the cell wall of clinical and laboratory isolates of Candida albicans. The INT1 gene encodes a protein of 1659 amino acids; the Int1 protein participates in adhesion to epithelial cells in vitro and in vivo. Int1 is essential for hyphal morphogenesis and virulence in a murine model. Recent evidence points to the amino terminus of Int1 as the source of a peptide, Pep263, with superantigen-like activities.

Biochemistry of Complement-Mediated Opsonization

Studies from the laboratory of Brian Tack were among the first to characterize the molecular mechanism by which the third component of complement, C3, binds covalently to free hydroxyl or amino groups. The glutamyl residue of the thiolester peptide 1009Gly-Cys-Gly-Glu-Gln1013 donates its carbonyl group in a transacylation reaction to form either an oxy-ester bond with carbohydrate acceptors or an amide bond with amino acceptors. In the absence of such acceptors, the thiolester site binds water at the glutamyl carbonyl, forming carboxylic acid and rendering the protein incapable of further covalent interaction [1].

The internal thiolester bond of C3 links Cys1010 and Gln1013 residues within the labile binding site of native C3, which is situated within the C3d subdomain of the α-chain of C3. This site is exposed when convertases of the classical, MBL, or alternative pathways cleave the C3a moiety from the amino terminus of the C3 α chain, and within the next 60 microseconds, the reactive glutamyl carbonyl in C3b is able to bind to carbohydrate or amino acceptors (Figure 1).

Figure 1.

Figure 1

Open in a new tab

Diagram of Opsonization (left panel), in which C3b is covalently deposited. Cleavage to iC3b exposes a binding site for attachment of neutrophil CR3, and phagocytosis ensues (center panel). Non-covalent binding of iC3b to Candida albicans perturbs CR3-mediated phagocytosis (right panel). Reprinted reference 9, with permission.

These reactions were shown to be applicable to the opsonization of Streptococcus pneumoniae [2] when Hostetter and colleagues demonstrated that reconstitution of the alternative complement pathway by the addition of purified C3 to human serum in which C3 and C4 were inactivated led to phagocytosis of 50-80% of pneumococcal serotypes 4, 6A, 14, or 18C, while the addition of preformed C3b (carboxylic acid at the reactive glutamyl carbonyl) or methylamine-treated C3 (amide bond occupying the reactive glutamyl carbonyl) resulted in phagocytosis of less than 7%. Once covalently bound to the pneumococcal surface, C3b was cleaved by factors H and I to generate the fragments iC3b and C3d, depending upon the pneumococcal serotype [3]. These results were generalized to group A streptococcus, E. coli, Staphylococcus aureus, and a number of other organisms [4-7].

Identification of an iC3b Receptor on Candida albicans

However, when Candida albicans was chosen as the organism to be opsonized, deposition of iC3b was non-covalent, like the reversible binding of iC3b to neutrophil complement receptor type 3 (CR3) [8, 9]. In C. albicans, non-covalent binding of iC3b inhibited phagocytosis, presumably because non-covalent binding of iC3b obscured the ligand binding site recognized by CR3 [Figure 1]. Complement receptor type 3 is also known as the integrin αM/β2 or CD11b/CD18. Binding of monoclonal antibodies recognizing the α-chain (OKM1, Mo1, M1/70), but not the β chain of αM/β2 suggested the expression of putative CR3-like receptors on the surface of clinical isolates of C. albicans [10]. Monoclonal antibodies against CR1 and CR2 did not bind to Candida albicans [9] [Figure 2].

Figure 2.

Figure 2

Open in a new tab

Histograms depicting binding of antibodies against complement receptors 1, 2, and 3 to C. albicans blastospores. Reprinted from reference 9, with permission.

The binding of [3H] iC3b was specific, saturable, and readily reversible in the presence of a 150-fold molar excess of unlabeled C3 [Figure 3] [9]. For two candidal isolates, the association constant (Ka) was similar at 2.45×106L/M, a determination very nearly identical to the Ka for the binding of iC3b to neutrophil CR3 [11]. In addition, expression of the putative receptor was significantly increased by hyphal transformation and by growth in the presence of 20-50 mM D-glucose [9]. Blockade of the putative candidal receptor by the IgM monoclonal antibody Mo1 increased phagocytosis significantly [9]. Subsequently, a number of monoclonal antibodies recognizing receptors for iC3b [9, 12-14] were shown to bind to C. albicans, suggesting that protein(s) on the C. albicans surface might share some structural homology with the α-chains of the leukocyte integrins CD11b/CD18 or Cd11c/CD18 (CR4 or αX/β2).

Figure 3.

Figure 3

Open in a new tab

Saturable binding curves for the non-covalent binding of purified iC3b to the surface of C. albicans blastospores from blood isolates 296 (left) and 311 (right). Reprinted from reference 9, with permission.

The α̃-chains of αM and αX have masses of 165 and 150 kDa, respectively, and share approximately 70% sequence homology, as well as an inserted or I domain of approximately 200 amino acids that is involved in ligand binding [15, 16]. In addition, located just C-terminal to the I domain in αM /αX are three divalent cation binding sites distinguished by the consensus sequence DXNS [17]. Distal to the transmembrane domain at the C terminus is a cytoplasmic tail with a single tyrosine residue [16]. Immunoprecipitation with 125I-labeled OKM1 or Western blotting with the monoclonal antibody Mo1 detected bands at Mr 130-165 kDa in extracts of cell wall, cell membrane, and cytosol from C. albicans blastospores [8, 18].

Role of the iC3b Receptor in Candidal Adhesion

The antigenic relationship between putative iC3b receptors on Candida albicans yeast cells and the leukocyte integrin α-chains CD11b or CD11c extended to functional similarities as well. CD11b/CD18 and its analog in C. albicans had an identical affinity for iC3b, and increased binding of monoclonal antibodies against CD11b occurred in both neutrophils and in yeast cells exposed to temperatures of 37°C.

Other conditions that increased expression of iC3b receptors in C. albicans (e.g. growth on 20 mM D-glucose as compared to 20 mM L-glutamate) augmented adhesion of yeast cells to human umbilical vein endothelium, as measured by flow cytometry with monoclonal antibodies recognizing CD11b increased significantly [19]. Blockade of C. albicans iC3b receptors with IgM monoclonal antibodies recognizing adhesive epitopes on neutrophil CD11b reduced adhesion to HUVE by 47%, while mouse IgM had no effect. Incubation of glucose-grown C. albicans with saturating concentrations of purified human iC3b, but not equimolar concentrations of BSA, also inhibited candidal adhesion to HUVE [19].

Surface expression of candidal iC3b receptors was highest in clinical and laboratory isolates of C. albicans, followed by C. tropicalis, C. parapsilosis, C. glabrata, C. lusitaniae, C. krusei, and S. cerevisiae and correlated with adhesion to monolayers of HeLaS3 cells, an epithelioid carcinoma cell line [20].

Subsequent studies identified a role for RGD tripeptides in epithelial adhesion of C. albicans and C. tropicalis, the two most adherent yeast species. Incubation of C. albicans with anti-αM monoclonal antibodies, with purified iC3b (which contains an RGD sequence), or with 9-15mer peptides encompassing the RGD sequence in iC3b inhibited epithelial adhesion significantly [21]. Purified fibronectin or RGD peptides from the fibronectin sequence failed to block C. albicans adhesion to HeLa cells, but significantly blocked the adhesion of C. tropicalis [21].

Cloning of the INT1 Gene and Structure of the Int1 Protein

The gene INT1 was identified from a C. albicans DNA library composed of 3.0-3.8 kbp EcoRI fragments by an initial screen with a 314 bp EcoRI/SmaI cDNA fragment derived from the transmembrane domain of human αM [22]. Two hybridizing clones contained a 3.5 kbp EcoRI insert and failed to hybridize with degenerate oligonucleotides from the S. cerevisiae gene USO1. A 500 bp HindIII subfragment from one of these clones was used to screen 20,000 clones from a library of C. albicans 10261 genomic DNA. The largest hybridizing insert, a 10.5 kbp SalI fragment, was isolated by agarose gel electropheresis, cloned, and sequenced. Analysis of the nucleotide sequence revealed an open reading frame sufficient to encode a 1661 residue polypeptide with a theoretical molecular mass of 187,989 Daltons and no extensive homologies with other proteins in the 1995 database [22]. BESTFIT sequence analysis located a putative I domain at amino acids 230-470 and three potential, partial MIDAS motifs for the coordination of divalent cations. There was an RGD sequence at residues 1149-1151, and a tyrosine residue at aa 1635, distal to a putative membrane-spanning region [22]. A pleckstrin homology domain at the C-terminus (aa 1529-1632) had no apparent function [23, 24] [ Figure 4].

Figure 4.

Figure 4

Open in a new tab

Diagram of putative and proven functional sites in the C. albicans cell wall protein Int1. Amino acids 1-263 comprise the superantigen Pep263. 239MHC254 is the region that shares homology with the MHC Class II binding site in the Mycoplasma arhtritidis superantigen. D-H-N-S are putative MIDAS motifs. 1149RGD1151 is a site that mediates binding to epithelial cells.

Functions of Int1

Adhesion

Our first approach was to express Int1 in the non-adherent yeast Saccharomyces cerevisiae [25]. We reasoned that C. albicans might have many adhesins (more than 20 now identified) and that a mutant deficient in just one might have no detectable loss of adhesion. S. cerevisiae transformed with vector alone was poorly adherent (<10%) to HeLa cells, while S. cerevisiae expressing Int1 adhered almost as well as wild type C. albicans (30% vs. 42%). Disruption of both copies of INT1 in C. albicans reduced adhesion, which could be blocked in both wild type C. albicans and in S. cerevisiae by antibodies against Int1 [25].

Hyphal Morphogenesis

Surprisingly, S. cerevisiae expressing INT1 grew in filamentous form, like C. albicans hyphae. Moreover, disruption of both copies of INT1 in C. albicans completely inhibited filamentation on solid medium. Filamentous growth was restored by reintegration of one copy of INT1 [25].

Virulence in a Murine Model

In a tail-vein injection model in outbred ICR mice, wild type C. albicans with two copies of INT1 was associated with 0% survival, while the double disruptant (Δint1) permitted 90% survival. Mice injected with either the heterozygote (INT1/int1) or the reintegrant (int1/int1/INT1) displayed intermediate survival (30-40%). Subsequently, C. albicans mutants disrupted for INT1 exhibited decreased ability to colonize the murine intestinal tract [26, 27].

Int1-Dependent Superantigen Effects

So why does the presence of INT1 kill mice? Patients with candidemia exhibit many of the findings of systemic inflammatory response syndrome: sustained fever, hypotension, and elevated levels of pro-inflammatory cytokines such as TNFα and IFNγ [28-30]. We therefore sought an Int1-dependent toxin that elicits a potent inflammatory response.

Because the amino terminus of Int1 had 56% identity with the MHC Class II binding site of Mycoplasma arthritidis molecule (MAM), a well-characterized superantigen [31], initial studies examined the ability of wild type C. albicans (Int1+) and an INT1 double disruptant (Int1-) to activate human T lymphocytes, expand particular Vβ subsets, and elicit pro-inflammatory cytokines.

In co-culture with PBMC's from five adult donors, the Int1+ strain was associated with up-regulation of the IL-2 receptor (CD25) in all donors; isogenic Int1- mutants were inactive [32]. These effects were statistically significant on days 4-7 (p<0.02). Two Int1+ strains and their respective reintegrants activated T lymphocytes, as measured by expression of CD25 and CD69. Int1- isogenic strains were significantly less active (p<0.002). Both CD4+ and CD8+ cells were activated, as were CD4+/CD8+ double positive cells; a similar pattern was noted with staphylococcal enterotoxin B, which served as a control superantigen. These effects required the presence of antigen-presenting cells and were not inhibited by paraformaldehyde.

All donors expanded Vβ subsets 2, 3 or 14 in Int1-dependent fashion [32]. One donor also expanded Vβ7.1. Expansion of Vβ subsets by Int1- cells was not observed. More than 75% of Vβ2 and Vβ14 T cells also expressed CD25, confirming that expansion correlated with activation. Both Int1+ and Int1- cells elicited TNFα and IL-6; however, only Int1+ cells elicited IFNγ. IFNγ is therefore the Int1-dependent cytokine. Neither IL-4 nor IL-10 was detected in response to Int1+ or Int1- C. albicans. MAb 163.5, a murine IgG1 raised to linear peptides spanning amino acids 239-278 of Int1, significantly inhibited T lymphocyte activation, expansion of Vβ subsets 2 and 14, and production of IFNγ [32].

When the first 263 amino acids of Int1 were expressed, this polypeptide (Pep263) also activated T lymphocytes, expanded Vβ subsets 2 and 14, and elicited IFNγ. These effects required the presence of Int1- blastospores and were significantly inhibited (50-70%) with 50 μg/ml of MAb 163.5, but not by an equal concentration of an irrelevant murine IgG1. Neither mAb 163.5 nor murine IgG1 inhibited T cell activation or expansion of the Vβ14 subset in response to staphylococcal enterotoxin B. Therefore, mAb 163.5 is specific for Int1 [32].

Native Pep263 concludes with the sequence 260KLKH263. The full-length construct of 263 amino acids activated T lymphocytes and expanded Vβ subsets 2 and 14, but truncation constructs ending in K262, L261 or K260 were no more active than medium alone. Substitution of A, D, or R for H263 did not restore activation of T lymphocytes or expansion of Vβ subsets 2 and 14 [32]. These results accord with the observation that mutation of key histidine residues in classical superantigens aborts their potency [33-35].

When antigen-presenting cells were examined by the binding of mannose-BSA as a marker for the mannose receptor (MR), an antibody against HLA-DR bound to 90.3% of these cells; however in the presence of biotinylated Pep263 the detection of HLA-DR was reduced more than 5-fold (from 90.3% to 15.9% of cells) [32]. Thus in the presence of Int1- blastospores, binding of Pep263 to antigen-presenting cells interferes with the detection of a class II antigen.

In the urine of a 43-day old premature infant with catheter-associated C. albicans fungemia, Western immunoblotting with mAb 163.5 detected immunoreactive bands at 44 and 22 kDa; bands of identical molecular weight were found when purified Pep263 was incubated in donor urine but were not present in uninfected urine. These results show that Pep263 can be generated in vivo [32].

Role of Heparin in Expression of the C. albicans Superantigen

The anti-coagulant heparin is commonly used to ensure patency of central venous catheters, which are identified as prime risk factors for candidemia in several clinical studies [36-38]. This clinical association led us to test whether heparin, in doses that one might use in an intravascular catheter, somehow augmented the expression of the candidal superantigen.

Our unpublished studies have shown that heparin does indeed trigger the exposure of Pep263, as measured by binding of monoclonal antibody 163.5. Exposure of Pep263 could be detected within 30 minutes. This phenomenon was reproduced with several other sulfated glycosaminoglycans [S.M. Kar, H Season, and M.K. Hostetter, unpublished data].

Binding of heparin, a strong anion, to proteins changes their conformation [39], and Int1 is readily accessible at the surface of the candidal cell wall. A search for heparin binding sequences (consensus sequence = BBXB, where B is any basic amino acid and X is any nonbasic/nonacidic amino acid) identified more than 15 at sites distal to Pep263 [K.G. Tan and M.K. Hostetter, unpublished data]. Heparin affinity chromatography enabled the heparin binding site to be mapped to a four amino acid sequence. Mutation of this site abrogated binding of biotinylated heparin and exposure of Pep263 [K.G. Tan and M.K. Hostetter, unpublished data].

Conclusions

Using biochemical and immunological techniques, we have identified a receptor for non-covalently bound iC3b in the cell wall of clinical and laboratory isolates of C. albicans. While initially demonstrated to play a role in RGD-mediated adhesion to epithelial cells and to inhibit phagocytosis, this protein, called Int1, is now known to contain a potent superantigen at its amino terminus (Pep263). Pep263 is exposed by heparin, is generated in vivo, and is inhibited by a monoclonal antibody, MAb 163.5.

Acknowledgments

This work was supported by grants from the National institutes of Health (1986-present) and the March of Dimes Foundation.

Footnotes

Conflict of Interest: From 2002-2005, Dr. Hostetter was the recipient of a research grant from Inhibitex (Alpharetta, GA), which led to the development of the monoclonal antibody 163.5. MAb 163.5 has been patented.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Hostetter MK, Thomas ML, Rosen FS, Tack BF. Binding of C3b proceeds by a transesterification reaction at the thiolester site. Nature. 1982 Jul 1;298(5869):72–5. doi: 10.1038/298072b0. [DOI] [PubMed] [Google Scholar]
  • 2.Hostetter MK, Krueger RA, Schmeling DJ. The biochemistry of opsonization: central role of the reactive thiolester of the third component of complement. J Infect Dis. 1984 Nov;150(5):653–61. doi: 10.1093/infdis/150.5.653. [DOI] [PubMed] [Google Scholar]
  • 3.Hostetter MK. Serotypic variations among virulent pneumococci in deposition and degradation of covalently bound C3b: implications for phagocytosis and antibody production. J Infect Dis. 1986 Apr;153(4):682–93. doi: 10.1093/infdis/153.4.682. [DOI] [PubMed] [Google Scholar]
  • 4.Gordon DL, Rice J, Finlay-Jones JJ, McDonald PJ, Hostetter MK. Analysis of C3 deposition and degradation on bacterial surfaces after opsonization. J Infect Dis. 1988 Apr;157(4):697–704. doi: 10.1093/infdis/157.4.697. [DOI] [PubMed] [Google Scholar]
  • 5.Correa AG, Baker CJ, Schutze GE, Edwards MS. Immunoglobulin G enhances C3 degradation on coagulase-negative staphylococci. Infect Immun. 1994 Jun;62(6):2362–6. doi: 10.1128/iai.62.6.2362-2366.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Campbell JR, Baker CJ, Edwards MS. Influence of serotype of group B streptococci on C3 degradation. Infect Immun. 1992 Nov;60(11):4558–62. doi: 10.1128/iai.60.11.4558-4562.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Campbell JR, Baker CJ, Edwards MS. Deposition and degradation of C3 on type III group B streptococci. Infect Immun. 1991 Jun;59(6):1978–83. doi: 10.1128/iai.59.6.1978-1983.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Heidenreich F, Dierich MP. Candida albicans and Candida stellatoidea, in contrast to other Candida species, bind iC3b and C3d but not C3b. Infect Immun. 1985 Nov;50(2):598–600. doi: 10.1128/iai.50.2.598-600.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Gilmore BJ, Retsinas EM, Lorenz JS, Hostetter MK. An iC3b receptor on Candida albicans: structure, function, and correlates for pathogenicity. J Infect Dis. 1988;157(1):38–46. doi: 10.1093/infdis/157.1.38. [DOI] [PubMed] [Google Scholar]
  • 10.Edwards JE, Jr, Gaither TA, O'Shea JJ, Rotrosen D, Lawley TJ, Wright SA, et al. Expression of specific binding sites on Candida with functional and antigenic characteristics of human complement receptors. J Immunol. 1986 Dec 1;137(11):3577–83. [PubMed] [Google Scholar]
  • 11.Gordon DL, Johnson GM, Hostetter MK. Characteristics of iC3b binding to human polymorphonuclear leucocytes. Immunology. 1987 Apr;60(4):553–8. [PMC free article] [PubMed] [Google Scholar]
  • 12.Moors MA, Stull TL, Blank KJ, Buckley HR, Mosser DM. A role for complement receptor-like molecules in iron acquisition by Candida albicans. J Exp Med. 1992 Jun 1;175(6):1643–51. doi: 10.1084/jem.175.6.1643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Ollert MW, Wadsworth E, Calderone RA. Reduced expression of the functionally active complement receptor for iC3b but not for C3d on an avirulent mutant of Candida albicans. Infect Immun. 1990 Apr;58(4):909–13. doi: 10.1128/iai.58.4.909-913.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Eigentler A, Schulz TF, Larcher C, Breitwieser EM, Myones BL, Petzer AL, et al. C3bi-binding protein on Candida albicans: temperature-dependent expression and relationship to human complement receptor type 3. Infect Immun. 1989 Feb;57(2):616–22. doi: 10.1128/iai.57.2.616-622.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Sanchez-Madrid F, Nagy JA, Robbins E, Simon P, Springer TA. A human leukocyte differentiation antigen family with distinct alpha-subunits and a common beta-subunit: the lymphocyte function-associated antigen (LFA-1), the C3bi complement receptor (OKM1/Mac-1), and the p150,95 molecule. J Exp Med. 1983 Dec 1;158(6):1785–803. doi: 10.1084/jem.158.6.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Corbi AL, Kishimoto TK, Miller LJ, Springer TA. The human leukocyte adhesion glycoprotein Mac-1 (complement receptor type 3, CD11b) alpha subunit. Cloning, primary structure, and relation to the integrins, von Willebrand factor and factor B. J Biol Chem. 1988 Sep 5;263(25):12403–11. [PubMed] [Google Scholar]
  • 17.Lee JO, Rieu P, Arnaout MA, Liddington R. Crystal structure of the A domain from the alpha subunit of integrin CR3 (CD11b/CD18) Cell. 1995 Feb 24;80(4):631–8. doi: 10.1016/0092-8674(95)90517-0. [DOI] [PubMed] [Google Scholar]
  • 18.Hostetter MK, Lorenz JS, Preus L, Kendrick KE. The iC3b receptor on Candida albicans: subcellular localization and modulation of receptor expression by glucose. J Infect Dis. 1990;161(4):761–8. doi: 10.1093/infdis/161.4.761. [DOI] [PubMed] [Google Scholar]
  • 19.Gustafson KS, Vercellotti GM, Bendel CM, Hostetter MK. Molecular mimicry in Candida albicans. Role of an integrin analogue in adhesion of the yeast to human endothelium. J Clin Invest. 1991;87(6):1896–902. doi: 10.1172/JCI115214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Bendel CM, St Sauver J, Carlson S, Hostetter MK. Epithelial adhesion in yeast species: correlation with surface expression of the integrin analog. J Infect Dis. 1995;171(6):1660–3. doi: 10.1093/infdis/171.6.1660. [DOI] [PubMed] [Google Scholar]
  • 21.Bendel CM, Hostetter MK. Distinct mechanisms of epithelial adhesion for Candida albicans and Candida tropicalis. Identification of the participating ligands and development of inhibitory peptides. J Clin Invest. 1993 Oct;92(4):1840–9. doi: 10.1172/JCI116775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Gale C, Finkel D, Tao N, Meinke M, McClellan M, Olson J, et al. Cloning and expression of a gene encoding an integrin-like protein in Candida albicans. Proc Natl Acad Sci U S A. 1996;93(1):357–61. doi: 10.1073/pnas.93.1.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Schultz J, Milpetz F, Bork P, Ponting CP. SMART, a simple modular architecture research tool: identification of signaling domains. Proc Natl Acad Sci U S A. 1998 May 26;95(11):5857–64. doi: 10.1073/pnas.95.11.5857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Gale C. Deletion of the pleckstrin homology domain in Int1 does not affect protein localization or morphology in Candida albicans. Pediatric Research (abstracts) 2004 May [Google Scholar]
  • 25.Gale CA, Bendel CM, McClellan M, Hauser M, Becker JM, Berman J, et al. Linkage of adhesion, filamentous growth, and virulence in Candida albicans to a single gene, INT1. Science. 1998;279(5355):1355–8. doi: 10.1126/science.279.5355.1355. [DOI] [PubMed] [Google Scholar]
  • 26.Kinneberg KM, Bendel CM, Jechorek RP, Cebelinski EA, Gale CA, Berman JG, et al. Effect of INT1 gene on Candida albicans murine intestinal colonization. J Surg Res. 1999;87(2):245–51. doi: 10.1006/jsre.1999.5755. [DOI] [PubMed] [Google Scholar]
  • 27.Bendel CM, Kinneberg KM, Jechorek RP, Erlandsen SL, Sahar DE, Wells CL. The Candida albicans INT1 gene facilitates cecal colonization in endotoxin-treated mice. Shock. 2000;13(6):453–8. doi: 10.1097/00024382-200006000-00006. [DOI] [PubMed] [Google Scholar]
  • 28.Braude AI, Rock JA. The syndrome of acute disseminated moniliasis in adults. AMA Arch Intern Med. 1959 Jul;104(1):91–100. doi: 10.1001/archinte.1959.00270070093012. [DOI] [PubMed] [Google Scholar]
  • 29.Presterl E, Lassnigg A, Mueller-Uri P, El-Menyawi I, Graninger W. Cytokines in sepsis due to Candida albicans and in bacterial sepsis. Eur Cytokine Netw. 1999 Sep;10(3):423–30. [PubMed] [Google Scholar]
  • 30.Chapman RL, Faix RG. Persistently positive cultures and outcome in invasive neonatal candidiasis. Pediatr Infect Dis J. 2000;19(9):822–7. doi: 10.1097/00006454-200009000-00003. [DOI] [PubMed] [Google Scholar]
  • 31.Cole BC, Knudtson KL, Oliphant A, Sawitzke AD, Pole A, Manohar M, et al. The sequence of the Mycoplasma arthritidis superantigen, MAM: identification of functional domains and comparison with microbial superantigens and plant lectin mitogens. J Exp Med. 1996 Mar 1;183(3):1105–10. doi: 10.1084/jem.183.3.1105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Devore-Carter D, Kar S, Vellucci V, Bhattacherjee V, Domanski P, Hostetter MK. Superantigen-like effects of a Candida albicans polypeptide. J Infect Dis. 2008 Apr 1;197(7):981–9. doi: 10.1086/529203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Al-Daccak R, Mehindate K, Damdoumi F, Etongue-Mayer P, Nilsson H, Antonsson P, et al. Staphylococcal enterotoxin D is a promiscuous superantigen offering multiple modes of interactions with the MHC class II receptors. J Immunol. 1998 Jan 1;160(1):225–32. [PubMed] [Google Scholar]
  • 34.Hoffman M, Tremaine M, Mansfield J, Betley M. Biochemical and mutational analysis of the histidine residues of staphylococcal enterotoxin A. Infect Immun. 1996 Mar;64(3):885–90. doi: 10.1128/iai.64.3.885-890.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Kokan-Moore NP, Bergdoll MS. Effect of chemical modification of histidine and tyrosine residues in toxic shock syndrome toxin 1 on the serologic and mitogenic activities of the toxin. Infect Immun. 1989 Jul;57(7):1901–5. doi: 10.1128/iai.57.7.1901-1905.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Nucci M, Colombo AL, Silveira F, Richtmann R, Salomao R, Branchini ML, et al. Risk factors for death in patients with candidemia. Infect Control Hosp Epidemiol. 1998;19(11):846–50. doi: 10.1086/647743. [DOI] [PubMed] [Google Scholar]
  • 37.Zaoutis TE, Coffin SE, Chu JH, Heydon K, Zhao H, Greves HM, et al. Risk factors for mortality in children with candidemia. Pediatr Infect Dis J. 2005 Aug;24(8):736–9. doi: 10.1097/01.inf.0000172938.76561.8e. [DOI] [PubMed] [Google Scholar]
  • 38.Saiman L, Ludington E, Pfaller M, Rangel-Frausto S, Wiblin RT, Dawson J, et al. Risk factors for candidemia in neonatal intensive care unit patients. Pediatr Infect Dis J. 2000;19(4):319–24. doi: 10.1097/00006454-200004000-00011. [DOI] [PubMed] [Google Scholar]
  • 39.Xiao K, Shenoy SK, Nobles K, Lefkowitz RJ. Activation-dependent conformational changes in beta-arrestin 2. J Biol Chem. 2004 Dec 31;279(53):55744–53. doi: 10.1074/jbc.M409785200. [DOI] [PubMed] [Google Scholar]

RESOURCES