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• W2103433414 abstract "Host infection by the pathogenic fungusCandida albicans is initiated by adhesion and mediated by binding to several host extracellular matrix proteins. Previously, we demonstrated that hemoglobin supplemented into a chemically defined medium significantly and specifically induced fibronectin binding toC. albicans. We now report that hemoglobin also induces binding of laminin, fibrinogen, and type IV collagen but not of thrombospondin-1 or type I collagen. The binding of each protein was inhibited by the respective unlabeled ligand in a concentration-dependent manner. Fibrinogen inhibited the binding of radiolabeled fibronectin, laminin, and fibrinogen with similar IC50 values, suggesting that a single promiscuous receptor recognizes these three proteins. Competitive binding studies indicated that a second class of receptor binds specifically to laminin. Growth of C. albicans in the presence of hemoglobin also increased cell adhesion to immobilized fibronectin, laminin, fibrinogen, and type IV collagen but not to thrombospondin-1 or type I collagen. Exposure to hemoglobin induced increased orde novo expression of several surface proteins on C. albicans. One of these proteins with a molecular weight of 55,000 recognized fibronectin, based on ligand protection and affinity chromatography on immobilized fibronectin. Thus, hemoglobin induces both promiscuous and specific receptors for extracellular matrix proteins and, therefore, may regulate matrix adhesion during dissemination of C. albicans infections. Host infection by the pathogenic fungusCandida albicans is initiated by adhesion and mediated by binding to several host extracellular matrix proteins. Previously, we demonstrated that hemoglobin supplemented into a chemically defined medium significantly and specifically induced fibronectin binding toC. albicans. We now report that hemoglobin also induces binding of laminin, fibrinogen, and type IV collagen but not of thrombospondin-1 or type I collagen. The binding of each protein was inhibited by the respective unlabeled ligand in a concentration-dependent manner. Fibrinogen inhibited the binding of radiolabeled fibronectin, laminin, and fibrinogen with similar IC50 values, suggesting that a single promiscuous receptor recognizes these three proteins. Competitive binding studies indicated that a second class of receptor binds specifically to laminin. Growth of C. albicans in the presence of hemoglobin also increased cell adhesion to immobilized fibronectin, laminin, fibrinogen, and type IV collagen but not to thrombospondin-1 or type I collagen. Exposure to hemoglobin induced increased orde novo expression of several surface proteins on C. albicans. One of these proteins with a molecular weight of 55,000 recognized fibronectin, based on ligand protection and affinity chromatography on immobilized fibronectin. Thus, hemoglobin induces both promiscuous and specific receptors for extracellular matrix proteins and, therefore, may regulate matrix adhesion during dissemination of C. albicans infections. Candida albicans is an important opportunistic pathogen for humans, causing both superficial and disseminated infections (reviewed in Refs. 1Odds F.C. J. Am. Acad. Dermatol. 1994; 31: S2-S5Abstract Full Text PDF PubMed Scopus (194) Google Scholar and 2Odds F. ASM News. 1994; 60: 313-318Google Scholar) with significant morbidity and mortality among immunocompromised patients (3Calderone R. Braun P. Microbiol. Rev. 1991; 55: 1-20Crossref PubMed Google Scholar). Adhesion of the organism to mucosal epithelium is a prerequisite for colonization and, therefore, is regarded as an initial step in the process leading to infections (3Calderone R. Braun P. Microbiol. Rev. 1991; 55: 1-20Crossref PubMed Google Scholar,4Segal E. Microbiol. Rev. 1987; 4: 344-347Google Scholar). Additional adhesion events to endothelium and extracellular matrix (ECM) 1The abbreviations used are: ECM, extracellular matrix; BSA, bovine serum albumin; FN, fibronectin; DPBS, Dulbecco's phosphate-buffered saline; sulfo-SHPP: sulfosuccinimidyl-3-(4-hydroxyphenyl) propionate; YNB, yeast nitrogen base. 1The abbreviations used are: ECM, extracellular matrix; BSA, bovine serum albumin; FN, fibronectin; DPBS, Dulbecco's phosphate-buffered saline; sulfo-SHPP: sulfosuccinimidyl-3-(4-hydroxyphenyl) propionate; YNB, yeast nitrogen base. components are required for dissemination of C. albicans. A number of ECM proteins bind to C. albicans, including fibronectin (5Klotz S.A. Hein R.C. Smith R.L. Rouse J.B. Infect. Immun. 1994; 62: 4679-4681Crossref PubMed Google Scholar, 6Negre E. Vogel T. Levanon A. Guy R. Walsh T.J. Roberts D.D. J. Biol. Chem. 1994; 269: 22039-22045Abstract Full Text PDF PubMed Google Scholar, 7Klotz S.A. Smith R.L. Microbiology (Washington D C). 1995; 141: 2681-2684PubMed Google Scholar, 8Klotz S. Smith R. J. Infect. Dis. 1991; 163: 604-610Crossref PubMed Scopus (97) Google Scholar), laminin (9Bouchara J. Tronchin G. Annaix V. Robert R. Senet J. Infect. Immun. 1990; 58: 48-54Crossref PubMed Google Scholar), vitronectin (10Jakab E. Paulsson M. Ascecio F. Ljunch A. APMIS. 1992; 101: 187-193Crossref Scopus (46) Google Scholar, 11Limper A.H. Standing J.E. Immunol. Lett. 1994; 42: 139-144Crossref PubMed Scopus (24) Google Scholar), complement (12Calderone R. Diamond R. Senet J.M. Warmington J. Filler S. Edwards J.E. J. Med. Vet. Mycol. 1994; 32: 151-168Crossref PubMed Scopus (44) Google Scholar), fibrinogen (13Casanova M. Lopez-Ribot J.L. Monteagudo C. Llombart-Bosch A. Sentandreu R. Martinez J.P. Infect. Immun. 1992; 60: 4221-4229Crossref PubMed Google Scholar), gelatin (7Klotz S.A. Smith R.L. Microbiology (Washington D C). 1995; 141: 2681-2684PubMed Google Scholar), and types I and IV collagen (14Klotz S.A. Rutten M.J. Smith R.L. Babcock S.R. Cunningham M.D. Microb. Pathog. 1993; 14: 133-147Crossref PubMed Scopus (54) Google Scholar).Interaction with individual ECM proteins is mediated by binding to respective receptors on the surface of Candida cells (5Klotz S.A. Hein R.C. Smith R.L. Rouse J.B. Infect. Immun. 1994; 62: 4679-4681Crossref PubMed Google Scholar, 6Negre E. Vogel T. Levanon A. Guy R. Walsh T.J. Roberts D.D. J. Biol. Chem. 1994; 269: 22039-22045Abstract Full Text PDF PubMed Google Scholar, 7Klotz S.A. Smith R.L. Microbiology (Washington D C). 1995; 141: 2681-2684PubMed Google Scholar,9Bouchara J. Tronchin G. Annaix V. Robert R. Senet J. Infect. Immun. 1990; 58: 48-54Crossref PubMed Google Scholar, 10Jakab E. Paulsson M. Ascecio F. Ljunch A. APMIS. 1992; 101: 187-193Crossref Scopus (46) Google Scholar, 11Limper A.H. Standing J.E. Immunol. Lett. 1994; 42: 139-144Crossref PubMed Scopus (24) Google Scholar). Some of these receptors are probably homologs of mammalian integrins (15Hostetter M.K. Pediatr. Res. 1996; 39: 569-573Crossref PubMed Scopus (12) Google Scholar). However, fibronectin binds to C. albicansboth through the cell binding domain recognized by mammalian integrins (8Klotz S. Smith R. J. Infect. Dis. 1991; 163: 604-610Crossref PubMed Scopus (97) Google Scholar) and through the collagen binding domain (6Negre E. Vogel T. Levanon A. Guy R. Walsh T.J. Roberts D.D. J. Biol. Chem. 1994; 269: 22039-22045Abstract Full Text PDF PubMed Google Scholar), and laminin and fibrinogen bind to distinct classes of receptors on C. albicans that are probably not integrins (9Bouchara J. Tronchin G. Annaix V. Robert R. Senet J. Infect. Immun. 1990; 58: 48-54Crossref PubMed Google Scholar, 13Casanova M. Lopez-Ribot J.L. Monteagudo C. Llombart-Bosch A. Sentandreu R. Martinez J.P. Infect. Immun. 1992; 60: 4221-4229Crossref PubMed Google Scholar, 16Lopez-Ribot J. Casanova M. Monteagudo C. Sepulveda P. Martinez J. Infect. Immun. 1994; 62: 742-746Crossref PubMed Google Scholar). Thus, both integrin and non-integrin receptors may mediate adhesion of C. albicans.Previously, we reported that hemoglobin induces a marked enhancement of fibronectin binding activity in C. albicans (17Yan S. Negre E. Cashel J.A. Guo N. Lyman C.A. Walsh T.J. Roberts D.D. Infect. Immun. 1996; 64: 2930-2935Crossref PubMed Google Scholar). This induction is reversible, requires cell growth in the presence of hemoglobin, and is not due to a bridge effect of hemoglobin between a receptor on the organism and fibronectin. In addition, adhesion of C. albicans to corneal endothelial cells was significantly increased when grown in hemoglobin-containing defined medium compared with those grown in defined medium alone. Although the ability to acquire iron has long been considered one of the most important adaptive responses for microbial pathogenesis (18Esterly N. Brammer S. Crounse R. J. Invest. Dermatol. 1967; 49: 437-442Abstract Full Text PDF PubMed Scopus (53) Google Scholar, 19Weinberg E. Microbiol. Rev. 1978; 42: 45-66Crossref PubMed Google Scholar), the enhancement of fibronectin binding by hemoglobin was not simply due to iron acquisition from the hemoglobin, because other ferroproteins, ferrous ions, or iron-containing porphyrins were inactive (17Yan S. Negre E. Cashel J.A. Guo N. Lyman C.A. Walsh T.J. Roberts D.D. Infect. Immun. 1996; 64: 2930-2935Crossref PubMed Google Scholar). Thus, hemoglobin itself may act as a potent regulator for the fibronectin receptor in C. albicans, although its precise mechanism remains unclear.We have now examined whether this specific induction by hemoglobin influences binding of C. albicans to other ECM proteins. We demonstrate that binding of C. albicans to laminin, fibrinogen, and type IV collagen, are increased to various degrees, but binding to thrombospondin-1 and type I collagen are not. In addition to inducing specific receptors for some ECM ligands on C. albicans, growth in the presence of hemoglobin induces a promiscuous receptor for several ECM proteins including fibronectin (FN), fibrinogen, and laminin. Adhesion to these proteins is also coordinately increased, and expression of specific cell surface proteins that bind FN is increased. Among these, a 55-kDa protein was identified as a hemoglobin-induced fibronectin receptor. Based on these findings, hemoglobin seems to be a potent regulator of the adhesive phenotype of C. albicans.DISCUSSIONBoth solution phase cell binding assays and adhesion to immobilized extracellular matrix proteins demonstrate that growth of C. albicans in a defined medium containing hemoglobin coordinately up-regulates interactions with laminin, fibronectin, fibrinogen, and type IV collagen. This up-regulation is specific in that interactions with at least two other extracellular matrix proteins, type I collagen and thrombospondin-1 are unaffected. Both binding to the proteins in solution and adhesion to the immobilized proteins are increased by growth in the presence of hemoglobin. A larger increase was observed in binding to the soluble proteins than in adhesion to immobilized proteins. This was noted previously using fibronectin (17Yan S. Negre E. Cashel J.A. Guo N. Lyman C.A. Walsh T.J. Roberts D.D. Infect. Immun. 1996; 64: 2930-2935Crossref PubMed Google Scholar) and probably reflects a greater sensibility of soluble ligand binding assays to changes in receptor number compared with the multivalent avidity measured in adhesion assays. Growth in the presence of hemoglobin induced increased expression of several proteins on the surface of C. albicans. FN binding to C. albicansprotected amino groups on a 55-kDa protein from chemical modification, identifying this surface protein as a candidate for the hemoglobin-induced ECM receptor. A 55-kDa protein was also identified as a potential FN receptor by purification using affinity chromatography on immobilized FN.To address whether a single promiscuous receptor or a family of receptors with varying specificities are responsible for the enhancement of ECM protein binding by hemoglobin, we performed quantitative analysis of heterologous displacement experiments. By comparing the Ki values for a single protein to inhibit binding of the three labeled proteins, fibronectin, laminin, and fibrinogen, we demonstrated that fibronectin and fibrinogen bind to a common class of sites that overlap only partially with those sites recognizing laminin. Therefore, growth in the presence of hemoglobin induces expression on C. albicans of a class of promiscuous receptors that bind fibronectin, fibrinogen, laminin, and type IV collagen and specific receptors for some ECM proteins, such as laminin. Binding of both fibronectin and fibrinogen to the promiscuous site produces a linear Scatchard plot, indicating that a homogeneous class of receptors accounts for binding of each of these ligands. Because some of these ECM proteins bind to each other, we could not examine heterologous displacement between all pairs of proteins. Using fibrinogen as a tracer for binding to the promiscuous receptor, however, we can show that native type I collagen does not bind to this receptor. Although C. albicans apparently has receptors that mediate adhesion to type I collagen and thrombospondin-1, these receptors are probably distinct from the promiscuous receptor because their binding and ability to promote adhesion are not affected by growth with hemoglobin.Studies in other organisms provide precedent for both specific and shared promiscuous receptors for ECM proteins. Promiscuous integrins have been identified in mammalian cells. The best defined of these are the platelet integrin IIbIIIa (αIIb/β3), which binds to fibrinogen, thrombospondin, fibronectin, and von Willebrand factor (25Yamada K. J. Biol. Chem. 1991; 266: 12809-12812Abstract Full Text PDF PubMed Google Scholar), and the leukocyte β2 integrin CR3 (CD11b/CD18, reviewed in Ref. 26Thornton B.P. Vetvicka V. Pitman M. Goldman R.C. Ross G.D. J. Immunol. 1996; 156: 1235-1246PubMed Google Scholar). Mammalian cells also express several families of scavenger receptors that bind multiple ligands (27Krieger M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Crossref PubMed Scopus (1057) Google Scholar). Among these, the low density lipoprotein receptor-related protein and CD36 have been demonstrated to bind to several ECM proteins (28Mikhailenko I. Kounnas M.Z. Strickland D.K. J. Biol. Chem. 1995; 270: 9543-9549Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 29Asch A.S. Barnwell J. Silverstein R.L. Nachman R.L. J. Clin. Invest. 1987; 79: 1054-1061Crossref PubMed Scopus (366) Google Scholar, 30Tandon N.N. Kralisz U. Jamieson G.A. J. Biol. Chem. 1989; 264: 7576-7583Abstract Full Text PDF PubMed Google Scholar). Microbial interactions with multiple ECM proteins are also frequently observed.Staphylococcus aureus interacts with fibronectin, laminin, collagens, thrombospondin-1, and elastin (31Park P. Roberts D. Grosso L. Park W. Rosenbloom J. Abrams W. Mecham R. J. Biol. Chem. 1991; 266: 23399-23406Abstract Full Text PDF PubMed Google Scholar) reviewed in (32Roberts D. Am. J. Respir. Cell Mol. Biol. 1990; 3: 181-186Crossref PubMed Scopus (21) Google Scholar, 33Patti J.M. Hook M. Curr. Opin. Cell Biol. 1994; 6: 752-758Crossref PubMed Scopus (197) Google Scholar). Some of these interactions are mediated by distinct receptors, but aS. aureus protein that binds several ECM proteins has also been reported (34McGavin M. Krajewska-Pictrasik D. Ryden C. Hook M. Infect. Immun. 1993; 61: 2479-2485Crossref PubMed Google Scholar). Blood stages of the protozoan pathogen responsible for malaria, Plasmodium falciparum, recognize the host proteins thrombospondin-1, CD36, VCAM1, E-selectin, and ICAM1 via a family of related cell surface receptors (35Borst P. Bitter W. McCulloch R. Van Leeuwen F. Rudenko G. Cell. 1995; 82: 1-4Abstract Full Text PDF PubMed Scopus (115) Google Scholar). The promiscuous receptor on C. albicans resembles a mammalian cell scavenger receptor (27Krieger M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Crossref PubMed Scopus (1057) Google Scholar) in that the proteins bound are apparently unrelated in sequence, but only a subset of proteins are recognized by the receptor.Previous studies of extracellular matrix interactions with C. albicans have identified candidate receptors for fibronectin (5Klotz S.A. Hein R.C. Smith R.L. Rouse J.B. Infect. Immun. 1994; 62: 4679-4681Crossref PubMed Google Scholar,8Klotz S. Smith R. J. Infect. Dis. 1991; 163: 604-610Crossref PubMed Scopus (97) Google Scholar), laminin (16Lopez-Ribot J. Casanova M. Monteagudo C. Sepulveda P. Martinez J. Infect. Immun. 1994; 62: 742-746Crossref PubMed Google Scholar), fibrinogen (36Lopez-Ribot J. Martinez J. Chaffin W. Infect. Immun. 1995; 63: 2126-2132Crossref PubMed Google Scholar), and entactin (37Lopez-Ribot J.L. Chaffin W.L. Infect. Immun. 1994; 62: 4564-4571Crossref PubMed Google Scholar) and an analog of mammalian integrin β subunits that may mediate adhesion to epithelial cells (reviewed in Ref. 15Hostetter M.K. Pediatr. Res. 1996; 39: 569-573Crossref PubMed Scopus (12) Google Scholar). Limited evidence has been obtained for partial competition between laminin, fibronectin, and entactin for binding to cell wall extracts of C. albicans (37Lopez-Ribot J.L. Chaffin W.L. Infect. Immun. 1994; 62: 4564-4571Crossref PubMed Google Scholar). However, no competition was observed between fibrinogen and the complement receptor (36Lopez-Ribot J. Martinez J. Chaffin W. Infect. Immun. 1995; 63: 2126-2132Crossref PubMed Google Scholar). Heparin inhibited binding of C. albicans to several ECM proteins, including fibronectin, laminin, and types I and IV collagen. This inhibition does not reflect binding of the glycosaminoglycans to a C. albicans binding site shared with these proteins but probably resulted from sequestration of ligands after binding of heparin to the proteins (38Klotz S.A. Smith R.L. FEMS Microbiol. Lett. 1992; 78: 205-208Crossref PubMed Scopus (16) Google Scholar).Up-regulated expression of potential receptors for selected ECM proteins was observed at the functional level by increased binding activity and adhesion to the immobilized proteins as well as at the protein level as increased expression of several surface proteins onC. albicans, including a 55-kDa protein. Binding of FN to the cells differentially protected the protein from chemical modification (Fig. 7), suggesting that it may directly mediate hemoglobin-induced interactions with fibronectin. The same 55-kDa protein was also identified as a major protein bound to a FN affinity column and eluted with acetic acid. Proteins of 68–72 kDa were identified previously as putative receptors for laminin, fibrinogen, and C3d (9Bouchara J. Tronchin G. Annaix V. Robert R. Senet J. Infect. Immun. 1990; 58: 48-54Crossref PubMed Google Scholar) and are reviewed in (3Calderone R. Braun P. Microbiol. Rev. 1991; 55: 1-20Crossref PubMed Google Scholar). Proteins with molecular masses of 60 and 105 kDa were identified as potential FN receptors in uninducedC. albicans by affinity chromatography on immobilized FN (5Klotz S.A. Hein R.C. Smith R.L. Rouse J.B. Infect. Immun. 1994; 62: 4679-4681Crossref PubMed Google Scholar,14Klotz S.A. Rutten M.J. Smith R.L. Babcock S.R. Cunningham M.D. Microb. Pathog. 1993; 14: 133-147Crossref PubMed Scopus (54) Google Scholar). Because lyticase was used to release the surface proteins, protease contamination in the lyticase could result in some degradation of the receptor. Thus, the native molecular mass of the receptor identified here may be larger than 55 kDa.The finding that hemoglobin is a potent regulator of the binding of C. albicans to several ECM proteins may contribute to understanding the pathogenesis of systemic candidasis. Hemoglobin is an abundant circulating protein in the body, and it is often present in sites of tissue injury. C. albicans may readily encounter hemoglobin at sites of tissue injury, which may in turn change its binding to ECM proteins in the tissue. Furthermore, virulent strains of C. albicans express a hemolytic activity that could release hemoglobin from erythrocytes exposed to C. albicans (39Manns J. Mosser D. Buckley H. Infect. Immun. 1994; 62: 5154-5156Crossref PubMed Google Scholar). Recently, hyphal cells of C. albicans were reported to bind to human hemoglobin, suggesting that this organism expresses hemoglobin receptors (40Watanabe T. Tanaka H. Nakao N. Mikami T. Matsumoto T. Biochem. Biophys. Res. Commun. 1997; 232: 350-353Crossref PubMed Scopus (34) Google Scholar). Induction of ECM binding to C. albicans by hemoglobin would facilitate colonization of this organism after it enters the vascular compartment. Therefore, defining of the mechanism by which hemoglobin regulates adherence in this pathogen could identify new targets to prevent or treat C. albicans infections. Candida albicans is an important opportunistic pathogen for humans, causing both superficial and disseminated infections (reviewed in Refs. 1Odds F.C. J. Am. Acad. Dermatol. 1994; 31: S2-S5Abstract Full Text PDF PubMed Scopus (194) Google Scholar and 2Odds F. ASM News. 1994; 60: 313-318Google Scholar) with significant morbidity and mortality among immunocompromised patients (3Calderone R. Braun P. Microbiol. Rev. 1991; 55: 1-20Crossref PubMed Google Scholar). Adhesion of the organism to mucosal epithelium is a prerequisite for colonization and, therefore, is regarded as an initial step in the process leading to infections (3Calderone R. Braun P. Microbiol. Rev. 1991; 55: 1-20Crossref PubMed Google Scholar,4Segal E. Microbiol. Rev. 1987; 4: 344-347Google Scholar). Additional adhesion events to endothelium and extracellular matrix (ECM) 1The abbreviations used are: ECM, extracellular matrix; BSA, bovine serum albumin; FN, fibronectin; DPBS, Dulbecco's phosphate-buffered saline; sulfo-SHPP: sulfosuccinimidyl-3-(4-hydroxyphenyl) propionate; YNB, yeast nitrogen base. 1The abbreviations used are: ECM, extracellular matrix; BSA, bovine serum albumin; FN, fibronectin; DPBS, Dulbecco's phosphate-buffered saline; sulfo-SHPP: sulfosuccinimidyl-3-(4-hydroxyphenyl) propionate; YNB, yeast nitrogen base. components are required for dissemination of C. albicans. A number of ECM proteins bind to C. albicans, including fibronectin (5Klotz S.A. Hein R.C. Smith R.L. Rouse J.B. Infect. Immun. 1994; 62: 4679-4681Crossref PubMed Google Scholar, 6Negre E. Vogel T. Levanon A. Guy R. Walsh T.J. Roberts D.D. J. Biol. Chem. 1994; 269: 22039-22045Abstract Full Text PDF PubMed Google Scholar, 7Klotz S.A. Smith R.L. Microbiology (Washington D C). 1995; 141: 2681-2684PubMed Google Scholar, 8Klotz S. Smith R. J. Infect. Dis. 1991; 163: 604-610Crossref PubMed Scopus (97) Google Scholar), laminin (9Bouchara J. Tronchin G. Annaix V. Robert R. Senet J. Infect. Immun. 1990; 58: 48-54Crossref PubMed Google Scholar), vitronectin (10Jakab E. Paulsson M. Ascecio F. Ljunch A. APMIS. 1992; 101: 187-193Crossref Scopus (46) Google Scholar, 11Limper A.H. Standing J.E. Immunol. Lett. 1994; 42: 139-144Crossref PubMed Scopus (24) Google Scholar), complement (12Calderone R. Diamond R. Senet J.M. Warmington J. Filler S. Edwards J.E. J. Med. Vet. Mycol. 1994; 32: 151-168Crossref PubMed Scopus (44) Google Scholar), fibrinogen (13Casanova M. Lopez-Ribot J.L. Monteagudo C. Llombart-Bosch A. Sentandreu R. Martinez J.P. Infect. Immun. 1992; 60: 4221-4229Crossref PubMed Google Scholar), gelatin (7Klotz S.A. Smith R.L. Microbiology (Washington D C). 1995; 141: 2681-2684PubMed Google Scholar), and types I and IV collagen (14Klotz S.A. Rutten M.J. Smith R.L. Babcock S.R. Cunningham M.D. Microb. Pathog. 1993; 14: 133-147Crossref PubMed Scopus (54) Google Scholar). Interaction with individual ECM proteins is mediated by binding to respective receptors on the surface of Candida cells (5Klotz S.A. Hein R.C. Smith R.L. Rouse J.B. Infect. Immun. 1994; 62: 4679-4681Crossref PubMed Google Scholar, 6Negre E. Vogel T. Levanon A. Guy R. Walsh T.J. Roberts D.D. J. Biol. Chem. 1994; 269: 22039-22045Abstract Full Text PDF PubMed Google Scholar, 7Klotz S.A. Smith R.L. Microbiology (Washington D C). 1995; 141: 2681-2684PubMed Google Scholar,9Bouchara J. Tronchin G. Annaix V. Robert R. Senet J. Infect. Immun. 1990; 58: 48-54Crossref PubMed Google Scholar, 10Jakab E. Paulsson M. Ascecio F. Ljunch A. APMIS. 1992; 101: 187-193Crossref Scopus (46) Google Scholar, 11Limper A.H. Standing J.E. Immunol. Lett. 1994; 42: 139-144Crossref PubMed Scopus (24) Google Scholar). Some of these receptors are probably homologs of mammalian integrins (15Hostetter M.K. Pediatr. Res. 1996; 39: 569-573Crossref PubMed Scopus (12) Google Scholar). However, fibronectin binds to C. albicansboth through the cell binding domain recognized by mammalian integrins (8Klotz S. Smith R. J. Infect. Dis. 1991; 163: 604-610Crossref PubMed Scopus (97) Google Scholar) and through the collagen binding domain (6Negre E. Vogel T. Levanon A. Guy R. Walsh T.J. Roberts D.D. J. Biol. Chem. 1994; 269: 22039-22045Abstract Full Text PDF PubMed Google Scholar), and laminin and fibrinogen bind to distinct classes of receptors on C. albicans that are probably not integrins (9Bouchara J. Tronchin G. Annaix V. Robert R. Senet J. Infect. Immun. 1990; 58: 48-54Crossref PubMed Google Scholar, 13Casanova M. Lopez-Ribot J.L. Monteagudo C. Llombart-Bosch A. Sentandreu R. Martinez J.P. Infect. Immun. 1992; 60: 4221-4229Crossref PubMed Google Scholar, 16Lopez-Ribot J. Casanova M. Monteagudo C. Sepulveda P. Martinez J. Infect. Immun. 1994; 62: 742-746Crossref PubMed Google Scholar). Thus, both integrin and non-integrin receptors may mediate adhesion of C. albicans. Previously, we reported that hemoglobin induces a marked enhancement of fibronectin binding activity in C. albicans (17Yan S. Negre E. Cashel J.A. Guo N. Lyman C.A. Walsh T.J. Roberts D.D. Infect. Immun. 1996; 64: 2930-2935Crossref PubMed Google Scholar). This induction is reversible, requires cell growth in the presence of hemoglobin, and is not due to a bridge effect of hemoglobin between a receptor on the organism and fibronectin. In addition, adhesion of C. albicans to corneal endothelial cells was significantly increased when grown in hemoglobin-containing defined medium compared with those grown in defined medium alone. Although the ability to acquire iron has long been considered one of the most important adaptive responses for microbial pathogenesis (18Esterly N. Brammer S. Crounse R. J. Invest. Dermatol. 1967; 49: 437-442Abstract Full Text PDF PubMed Scopus (53) Google Scholar, 19Weinberg E. Microbiol. Rev. 1978; 42: 45-66Crossref PubMed Google Scholar), the enhancement of fibronectin binding by hemoglobin was not simply due to iron acquisition from the hemoglobin, because other ferroproteins, ferrous ions, or iron-containing porphyrins were inactive (17Yan S. Negre E. Cashel J.A. Guo N. Lyman C.A. Walsh T.J. Roberts D.D. Infect. Immun. 1996; 64: 2930-2935Crossref PubMed Google Scholar). Thus, hemoglobin itself may act as a potent regulator for the fibronectin receptor in C. albicans, although its precise mechanism remains unclear. We have now examined whether this specific induction by hemoglobin influences binding of C. albicans to other ECM proteins. We demonstrate that binding of C. albicans to laminin, fibrinogen, and type IV collagen, are increased to various degrees, but binding to thrombospondin-1 and type I collagen are not. In addition to inducing specific receptors for some ECM ligands on C. albicans, growth in the presence of hemoglobin induces a promiscuous receptor for several ECM proteins including fibronectin (FN), fibrinogen, and laminin. Adhesion to these proteins is also coordinately increased, and expression of specific cell surface proteins that bind FN is increased. Among these, a 55-kDa protein was identified as a hemoglobin-induced fibronectin receptor. Based on these findings, hemoglobin seems to be a potent regulator of the adhesive phenotype of C. albicans. DISCUSSIONBoth solution phase cell binding assays and adhesion to immobilized extracellular matrix proteins demonstrate that growth of C. albicans in a defined medium containing hemoglobin coordinately up-regulates interactions with laminin, fibronectin, fibrinogen, and type IV collagen. This up-regulation is specific in that interactions with at least two other extracellular matrix proteins, type I collagen and thrombospondin-1 are unaffected. Both binding to the proteins in solution and adhesion to the immobilized proteins are increased by growth in the presence of hemoglobin. A larger increase was observed in binding to the soluble proteins than in adhesion to immobilized proteins. This was noted previously using fibronectin (17Yan S. Negre E. Cashel J.A. Guo N. Lyman C.A. Walsh T.J. Roberts D.D. Infect. Immun. 1996; 64: 2930-2935Crossref PubMed Google Scholar) and probably reflects a greater sensibility of soluble ligand binding assays to changes in receptor number compared with the multivalent avidity measured in adhesion assays. Growth in the presence of hemoglobin induced increased expression of several proteins on the surface of C. albicans. FN binding to C. albicansprotected amino groups on a 55-kDa protein from chemical modification, identifying this surface protein as a candidate for the hemoglobin-induced ECM receptor. A 55-kDa protein was also identified as a potential FN receptor by purification using affinity chromatography on immobilized FN.To address whether a single promiscuous receptor or a family of receptors with varying specificities are responsible for the enhancement of ECM protein binding by hemoglobin, we performed quantitative analysis of heterologous displacement experiments. By comparing the Ki values for a single protein to inhibit binding of the three labeled proteins, fibronectin, laminin, and fibrinogen, we demonstrated that fibronectin and fibrinogen bind to a common class of sites that overlap only partially with those sites recognizing laminin. Therefore, growth in the presence of hemoglobin induces expression on C. albicans of a class of promiscuous receptors that bind fibronectin, fibrinogen, laminin, and type IV collagen and specific receptors for some ECM proteins, such as laminin. Binding of both fibronectin and fibrinogen to the promiscuous site produces a linear Scatchard plot, indicating that a homogeneous class of receptors accounts for binding of each of these ligands. Because some of these ECM proteins bind to each other, we could not examine heterologous displacement between all pairs of proteins. Using fibrinogen as a tracer for binding to the promiscuous receptor, however, we can show that native type I collagen does not bind to this receptor. Although C. albicans apparently has receptors that mediate adhesion to type I collagen and thrombospondin-1, these receptors are probably distinct from the promiscuous receptor because their binding and ability to promote adhesion are not affected by growth with hemoglobin.Studies in other organisms provide precedent for both specific and shared promiscuous receptors for ECM proteins. Promiscuous integrins have been identified in mammalian cells. The best defined of these are the platelet integrin IIbIIIa (αIIb/β3), which binds to fibrinogen, thrombospondin, fibronectin, and von Willebrand factor (25Yamada K. J. Biol. Chem. 1991; 266: 12809-12812Abstract Full Text PDF PubMed Google Scholar), and the leukocyte β2 integrin CR3 (CD11b/CD18, reviewed in Ref. 26Thornton B.P. Vetvicka V. Pitman M. Goldman R.C. Ross G.D. J. Immunol. 1996; 156: 1235-1246PubMed Google Scholar). Mammalian cells also express several families of scavenger receptors that bind multiple ligands (27Krieger M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Crossref PubMed Scopus (1057) Google Scholar). Among these, the low density lipoprotein receptor-related protein and CD36 have been demonstrated to bind to several ECM proteins (28Mikhailenko I. Kounnas M.Z. Strickland D.K. J. Biol. Chem. 1995; 270: 9543-9549Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 29Asch A.S. Barnwell J. Silverstein R.L. Nachman R.L. J. Clin. Invest. 1987; 79: 1054-1061Crossref PubMed Scopus (366) Google Scholar, 30Tandon N.N. Kralisz U. Jamieson G.A. J. Biol. Chem. 1989; 264: 7576-7583Abstract Full Text PDF PubMed Google Scholar). Microbial interactions with multiple ECM proteins are also frequently observed.Staphylococcus aureus interacts with fibronectin, laminin, collagens, thrombospondin-1, and elastin (31Park P. Roberts D. Grosso L. Park W. Rosenbloom J. Abrams W. Mecham R. J. Biol. Chem. 1991; 266: 23399-23406Abstract Full Text PDF PubMed Google Scholar) reviewed in (32Roberts D. Am. J. Respir. Cell Mol. Biol. 1990; 3: 181-186Crossref PubMed Scopus (21) Google Scholar, 33Patti J.M. Hook M. Curr. Opin. Cell Biol. 1994; 6: 752-758Crossref PubMed Scopus (197) Google Scholar). Some of these interactions are mediated by distinct receptors, but aS. aureus protein that binds several ECM proteins has also been reported (34McGavin M. Krajewska-Pictrasik D. Ryden C. Hook M. Infect. Immun. 1993; 61: 2479-2485Crossref PubMed Google Scholar). Blood stages of the protozoan pathogen responsible for malaria, Plasmodium falciparum, recognize the host proteins thrombospondin-1, CD36, VCAM1, E-selectin, and ICAM1 via a family of related cell surface receptors (35Borst P. Bitter W. McCulloch R. Van Leeuwen F. Rudenko G. Cell. 1995; 82: 1-4Abstract Full Text PDF PubMed Scopus (115) Google Scholar). The promiscuous receptor on C. albicans resembles a mammalian cell scavenger receptor (27Krieger M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Crossref PubMed Scopus (1057) Google Scholar) in that the proteins bound are apparently unrelated in sequence, but only a subset of proteins are recognized by the receptor.Previous studies of extracellular matrix interactions with C. albicans have identified candidate receptors for fibronectin (5Klotz S.A. Hein R.C. Smith R.L. Rouse J.B. Infect. Immun. 1994; 62: 4679-4681Crossref PubMed Google Scholar,8Klotz S. Smith R. J. Infect. Dis. 1991; 163: 604-610Crossref PubMed Scopus (97) Google Scholar), laminin (16Lopez-Ribot J. Casanova M. Monteagudo C. Sepulveda P. Martinez J. Infect. Immun. 1994; 62: 742-746Crossref PubMed Google Scholar), fibrinogen (36Lopez-Ribot J. Martinez J. Chaffin W. Infect. Immun. 1995; 63: 2126-2132Crossref PubMed Google Scholar), and entactin (37Lopez-Ribot J.L. Chaffin W.L. Infect. Immun. 1994; 62: 4564-4571Crossref PubMed Google Scholar) and an analog of mammalian integrin β subunits that may mediate adhesion to epithelial cells (reviewed in Ref. 15Hostetter M.K. Pediatr. Res. 1996; 39: 569-573Crossref PubMed Scopus (12) Google Scholar). Limited evidence has been obtained for partial competition between laminin, fibronectin, and entactin for binding to cell wall extracts of C. albicans (37Lopez-Ribot J.L. Chaffin W.L. Infect. Immun. 1994; 62: 4564-4571Crossref PubMed Google Scholar). However, no competition was observed between fibrinogen and the complement receptor (36Lopez-Ribot J. Martinez J. Chaffin W. Infect. Immun. 1995; 63: 2126-2132Crossref PubMed Google Scholar). Heparin inhibited binding of C. albicans to several ECM proteins, including fibronectin, laminin, and types I and IV collagen. This inhibition does not reflect binding of the glycosaminoglycans to a C. albicans binding site shared with these proteins but probably resulted from sequestration of ligands after binding of heparin to the proteins (38Klotz S.A. Smith R.L. FEMS Microbiol. Lett. 1992; 78: 205-208Crossref PubMed Scopus (16) Google Scholar).Up-regulated expression of potential receptors for selected ECM proteins was observed at the functional level by increased binding activity and adhesion to the immobilized proteins as well as at the protein level as increased expression of several surface proteins onC. albicans, including a 55-kDa protein. Binding of FN to the cells differentially protected the protein from chemical modification (Fig. 7), suggesting that it may directly mediate hemoglobin-induced interactions with fibronectin. The same 55-kDa protein was also identified as a major protein bound to a FN affinity column and eluted with acetic acid. Proteins of 68–72 kDa were identified previously as putative receptors for laminin, fibrinogen, and C3d (9Bouchara J. Tronchin G. Annaix V. Robert R. Senet J. Infect. Immun. 1990; 58: 48-54Crossref PubMed Google Scholar) and are reviewed in (3Calderone R. Braun P. Microbiol. Rev. 1991; 55: 1-20Crossref PubMed Google Scholar). Proteins with molecular masses of 60 and 105 kDa were identified as potential FN receptors in uninducedC. albicans by affinity chromatography on immobilized FN (5Klotz S.A. Hein R.C. Smith R.L. Rouse J.B. Infect. Immun. 1994; 62: 4679-4681Crossref PubMed Google Scholar,14Klotz S.A. Rutten M.J. Smith R.L. Babcock S.R. Cunningham M.D. Microb. Pathog. 1993; 14: 133-147Crossref PubMed Scopus (54) Google Scholar). Because lyticase was used to release the surface proteins, protease contamination in the lyticase could result in some degradation of the receptor. Thus, the native molecular mass of the receptor identified here may be larger than 55 kDa.The finding that hemoglobin is a potent regulator of the binding of C. albicans to several ECM proteins may contribute to understanding the pathogenesis of systemic candidasis. Hemoglobin is an abundant circulating protein in the body, and it is often present in sites of tissue injury. C. albicans may readily encounter hemoglobin at sites of tissue injury, which may in turn change its binding to ECM proteins in the tissue. Furthermore, virulent strains of C. albicans express a hemolytic activity that could release hemoglobin from erythrocytes exposed to C. albicans (39Manns J. Mosser D. Buckley H. Infect. Immun. 1994; 62: 5154-5156Crossref PubMed Google Scholar). Recently, hyphal cells of C. albicans were reported to bind to human hemoglobin, suggesting that this organism expresses hemoglobin receptors (40Watanabe T. Tanaka H. Nakao N. Mikami T. Matsumoto T. Biochem. Biophys. Res. Commun. 1997; 232: 350-353Crossref PubMed Scopus (34) Google Scholar). Induction of ECM binding to C. albicans by hemoglobin would facilitate colonization of this organism after it enters the vascular compartment. Therefore, defining of the mechanism by which hemoglobin regulates adherence in this pathogen could identify new targets to prevent or treat C. albicans infections. Both solution phase cell binding assays and adhesion to immobilized extracellular matrix proteins demonstrate that growth of C. albicans in a defined medium containing hemoglobin coordinately up-regulates interactions with laminin, fibronectin, fibrinogen, and type IV collagen. This up-regulation is specific in that interactions with at least two other extracellular matrix proteins, type I collagen and thrombospondin-1 are unaffected. Both binding to the proteins in solution and adhesion to the immobilized proteins are increased by growth in the presence of hemoglobin. A larger increase was observed in binding to the soluble proteins than in adhesion to immobilized proteins. This was noted previously using fibronectin (17Yan S. Negre E. Cashel J.A. Guo N. Lyman C.A. Walsh T.J. Roberts D.D. Infect. Immun. 1996; 64: 2930-2935Crossref PubMed Google Scholar) and probably reflects a greater sensibility of soluble ligand binding assays to changes in receptor number compared with the multivalent avidity measured in adhesion assays. Growth in the presence of hemoglobin induced increased expression of several proteins on the surface of C. albicans. FN binding to C. albicansprotected amino groups on a 55-kDa protein from chemical modification, identifying this surface protein as a candidate for the hemoglobin-induced ECM receptor. A 55-kDa protein was also identified as a potential FN receptor by purification using affinity chromatography on immobilized FN. To address whether a single promiscuous receptor or a family of receptors with varying specificities are responsible for the enhancement of ECM protein binding by hemoglobin, we performed quantitative analysis of heterologous displacement experiments. By comparing the Ki values for a single protein to inhibit binding of the three labeled proteins, fibronectin, laminin, and fibrinogen, we demonstrated that fibronectin and fibrinogen bind to a common class of sites that overlap only partially with those sites recognizing laminin. Therefore, growth in the presence of hemoglobin induces expression on C. albicans of a class of promiscuous receptors that bind fibronectin, fibrinogen, laminin, and type IV collagen and specific receptors for some ECM proteins, such as laminin. Binding of both fibronectin and fibrinogen to the promiscuous site produces a linear Scatchard plot, indicating that a homogeneous class of receptors accounts for binding of each of these ligands. Because some of these ECM proteins bind to each other, we could not examine heterologous displacement between all pairs of proteins. Using fibrinogen as a tracer for binding to the promiscuous receptor, however, we can show that native type I collagen does not bind to this receptor. Although C. albicans apparently has receptors that mediate adhesion to type I collagen and thrombospondin-1, these receptors are probably distinct from the promiscuous receptor because their binding and ability to promote adhesion are not affected by growth with hemoglobin. Studies in other organisms provide precedent for both specific and shared promiscuous receptors for ECM proteins. Promiscuous integrins have been identified in mammalian cells. The best defined of these are the platelet integrin IIbIIIa (αIIb/β3), which binds to fibrinogen, thrombospondin, fibronectin, and von Willebrand factor (25Yamada K. J. Biol. Chem. 1991; 266: 12809-12812Abstract Full Text PDF PubMed Google Scholar), and the leukocyte β2 integrin CR3 (CD11b/CD18, reviewed in Ref. 26Thornton B.P. Vetvicka V. Pitman M. Goldman R.C. Ross G.D. J. Immunol. 1996; 156: 1235-1246PubMed Google Scholar). Mammalian cells also express several families of scavenger receptors that bind multiple ligands (27Krieger M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Crossref PubMed Scopus (1057) Google Scholar). Among these, the low density lipoprotein receptor-related protein and CD36 have been demonstrated to bind to several ECM proteins (28Mikhailenko I. Kounnas M.Z. Strickland D.K. J. Biol. Chem. 1995; 270: 9543-9549Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 29Asch A.S. Barnwell J. Silverstein R.L. Nachman R.L. J. Clin. Invest. 1987; 79: 1054-1061Crossref PubMed Scopus (366) Google Scholar, 30Tandon N.N. Kralisz U. Jamieson G.A. J. Biol. Chem. 1989; 264: 7576-7583Abstract Full Text PDF PubMed Google Scholar). Microbial interactions with multiple ECM proteins are also frequently observed.Staphylococcus aureus interacts with fibronectin, laminin, collagens, thrombospondin-1, and elastin (31Park P. Roberts D. Grosso L. Park W. Rosenbloom J. Abrams W. Mecham R. J. Biol. Chem. 1991; 266: 23399-23406Abstract Full Text PDF PubMed Google Scholar) reviewed in (32Roberts D. Am. J. Respir. Cell Mol. Biol. 1990; 3: 181-186Crossref PubMed Scopus (21) Google Scholar, 33Patti J.M. Hook M. Curr. Opin. Cell Biol. 1994; 6: 752-758Crossref PubMed Scopus (197) Google Scholar). Some of these interactions are mediated by distinct receptors, but aS. aureus protein that binds several ECM proteins has also been reported (34McGavin M. Krajewska-Pictrasik D. Ryden C. Hook M. Infect. Immun. 1993; 61: 2479-2485Crossref PubMed Google Scholar). Blood stages of the protozoan pathogen responsible for malaria, Plasmodium falciparum, recognize the host proteins thrombospondin-1, CD36, VCAM1, E-selectin, and ICAM1 via a family of related cell surface receptors (35Borst P. Bitter W. McCulloch R. Van Leeuwen F. Rudenko G. Cell. 1995; 82: 1-4Abstract Full Text PDF PubMed Scopus (115) Google Scholar). The promiscuous receptor on C. albicans resembles a mammalian cell scavenger receptor (27Krieger M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Crossref PubMed Scopus (1057) Google Scholar) in that the proteins bound are apparently unrelated in sequence, but only a subset of proteins are recognized by the receptor. Previous studies of extracellular matrix interactions with C. albicans have identified candidate receptors for fibronectin (5Klotz S.A. Hein R.C. Smith R.L. Rouse J.B. Infect. Immun. 1994; 62: 4679-4681Crossref PubMed Google Scholar,8Klotz S. Smith R. J. Infect. Dis. 1991; 163: 604-610Crossref PubMed Scopus (97) Google Scholar), laminin (16Lopez-Ribot J. Casanova M. Monteagudo C. Sepulveda P. Martinez J. Infect. Immun. 1994; 62: 742-746Crossref PubMed Google Scholar), fibrinogen (36Lopez-Ribot J. Martinez J. Chaffin W. Infect. Immun. 1995; 63: 2126-2132Crossref PubMed Google Scholar), and entactin (37Lopez-Ribot J.L. Chaffin W.L. Infect. Immun. 1994; 62: 4564-4571Crossref PubMed Google Scholar) and an analog of mammalian integrin β subunits that may mediate adhesion to epithelial cells (reviewed in Ref. 15Hostetter M.K. Pediatr. Res. 1996; 39: 569-573Crossref PubMed Scopus (12) Google Scholar). Limited evidence has been obtained for partial competition between laminin, fibronectin, and entactin for binding to cell wall extracts of C. albicans (37Lopez-Ribot J.L. Chaffin W.L. Infect. Immun. 1994; 62: 4564-4571Crossref PubMed Google Scholar). However, no competition was observed between fibrinogen and the complement receptor (36Lopez-Ribot J. Martinez J. Chaffin W. Infect. Immun. 1995; 63: 2126-2132Crossref PubMed Google Scholar). Heparin inhibited binding of C. albicans to several ECM proteins, including fibronectin, laminin, and types I and IV collagen. This inhibition does not reflect binding of the glycosaminoglycans to a C. albicans binding site shared with these proteins but probably resulted from sequestration of ligands after binding of heparin to the proteins (38Klotz S.A. Smith R.L. FEMS Microbiol. Lett. 1992; 78: 205-208Crossref PubMed Scopus (16) Google Scholar). Up-regulated expression of potential receptors for selected ECM proteins was observed at the functional level by increased binding activity and adhesion to the immobilized proteins as well as at the protein level as increased expression of several surface proteins onC. albicans, including a 55-kDa protein. Binding of FN to the cells differentially protected the protein from chemical modification (Fig. 7), suggesting that it may directly mediate hemoglobin-induced interactions with fibronectin. The same 55-kDa protein was also identified as a major protein bound to a FN affinity column and eluted with acetic acid. Proteins of 68–72 kDa were identified previously as putative receptors for laminin, fibrinogen, and C3d (9Bouchara J. Tronchin G. Annaix V. Robert R. Senet J. Infect. Immun. 1990; 58: 48-54Crossref PubMed Google Scholar) and are reviewed in (3Calderone R. Braun P. Microbiol. Rev. 1991; 55: 1-20Crossref PubMed Google Scholar). Proteins with molecular masses of 60 and 105 kDa were identified as potential FN receptors in uninducedC. albicans by affinity chromatography on immobilized FN (5Klotz S.A. Hein R.C. Smith R.L. Rouse J.B. Infect. Immun. 1994; 62: 4679-4681Crossref PubMed Google Scholar,14Klotz S.A. Rutten M.J. Smith R.L. Babcock S.R. Cunningham M.D. Microb. Pathog. 1993; 14: 133-147Crossref PubMed Scopus (54) Google Scholar). Because lyticase was used to release the surface proteins, protease contamination in the lyticase could result in some degradation of the receptor. Thus, the native molecular mass of the receptor identified here may be larger than 55 kDa. The finding that hemoglobin is a potent regulator of the binding of C. albicans to several ECM proteins may contribute to understanding the pathogenesis of systemic candidasis. Hemoglobin is an abundant circulating protein in the body, and it is often present in sites of tissue injury. C. albicans may readily encounter hemoglobin at sites of tissue injury, which may in turn change its binding to ECM proteins in the tissue. Furthermore, virulent strains of C. albicans express a hemolytic activity that could release hemoglobin from erythrocytes exposed to C. albicans (39Manns J. Mosser D. Buckley H. Infect. Immun. 1994; 62: 5154-5156Crossref PubMed Google Scholar). Recently, hyphal cells of C. albicans were reported to bind to human hemoglobin, suggesting that this organism expresses hemoglobin receptors (40Watanabe T. Tanaka H. Nakao N. Mikami T. Matsumoto T. Biochem. Biophys. Res. Commun. 1997; 232: 350-353Crossref PubMed Scopus (34) Google Scholar). Induction of ECM binding to C. albicans by hemoglobin would facilitate colonization of this organism after it enters the vascular compartment. Therefore, defining of the mechanism by which hemoglobin regulates adherence in this pathogen could identify new targets to prevent or treat C. albicans infections." @default.
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