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Role of Hyphal Formation in Interactions of Candida albicans with Endothelial Cells
Open accessAbstract
The ability to change from yeast to hyphal morphology is a major virulence determinant of Candida albicans . Mutants with defined defects in filamentation regulatory pathways have reduced virulence in mice. However, is it poorly understood why hyphal formation is critical for C. albicans to cause hematogenously disseminated infections. We used recently constructed mutants to examine the role of hyphal formation in the interactions of C. albicans with endothelial cells in vitro. These interactions included the ability of the mutants to invade and injure endothelial cells. Because the formation of hyphae may influence the host inflammatory response to C. albicans , we also investigated the capacity of these mutants to stimulate endothelial cells to express E-selectin and intercellular adhesion molecule 1. We infected endothelial cells with C. albicans strains containing homozygous null mutations in the following filamentation regulatory genes: CLA4 , CPH1 , EFG1 , and TUP1 . Whereas the wild-type strain formed true hyphae on endothelial cells, we found that neither the Δ efg1 nor the Δ cph1 Δefg1 double mutant germinated. The Δ tup1 mutant formed only pseudohyphae. We also found that the Δ efg1 , Δ cph1 Δefg1 , and Δ tup1 mutants had significantly reduced capacities to invade and injure endothelial cells. Therefore, Efg1p and Tup1p contribute to virulence by regulating hyphal formation and the factors that enable C. albicans to invade and injure endothelial cells. With the exception of the Δcph1 Δefg1 mutant, all other mutants stimulated endothelial cells to express at least one of the leukocyte adhesion molecules. Therefore, the combined activities of Cph1p and Efg1p are required for C. albicans to stimulate a proinflammatory response in endothelial cells.
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“Host cell invasion and damage are likely critical virulence attributes of C. albicans because mutants with defects in these processes in vitro are highly likely to have attenuated virulence in experimental animal models of hematogenously disseminated or oropharyngeal candidiasis [5][6][7][8].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [7]
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“Furthermore, studies with killed organisms indicate that induction of endocytosis is passive on the part of the organism because killed hyphae are endocytosed as avidly as are live hyphae [5,7].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [7]
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“We have found previously that C. albicans mutants with defects in the signal transduction pathways that govern hyphal formation have a significantly reduced capacity to invade both endothelial and oral epithelial cells in vitro [5][6][7].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [7]
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“Previously, we have found that C. albicans invades both endothelial cells and oral epithelial cells in vitro by inducing its own endocytosis [4,5,7].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [7]
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Cited by
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Saville, S. P., Lazzell, A. L., Monteagudo, C., & Lopez-Ribot, J. L. (2003) · Eukaryotic Cell · doi:10.1128/ec.2.5.1053-1060.2003 · Cited by 655
“It has been assumed that these few infecting cells had somehow managed to form filaments in vivo through an Efg1p/Cph1p-independent mechanism, possibly through activation of the transcription factor Czf1p (8, 12), which had enabled them to extravasate and disseminate to the organs, with supporting evidence for this pr…”
BackgroundAls3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells
Phan, Q. T., Myers, C. L., Fu, Y., Sheppard, D. C., Yeaman, M. R., Welch, W. H., Ibrahim, A. S., Edwards, J. E., & Filler, S. G. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050064 · Cited by 641
“Furthermore, studies with killed organisms indicate that induction of endocytosis is passive on the part of the organism because killed hyphae are endocytosed as avidly as are live hyphae [5,7].”
BackgroundMethodSelf-citationOral Candidiasis: A Disease of Opportunity
Vila, T., Sultan, A. S., Montelongo-Jauregui, D., & Jabra-Rizk, M. A. (2020) · Journal of Fungi · doi:10.3390/jof6010015 · Cited by 537
Candida albicans Cell Wall Proteins
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Fradin, C., De Groot, P., MacCallum, D., Schaller, M., Klis, F., Odds, F. C., & Hube, B. (2005) · Molecular Microbiology · doi:10.1111/j.1365-2958.2005.04557.x · Cited by 455
“…to adhere to endothelial cells (Rotrosen et al., 1985) and hyphal cells, but not yeast cells, have been shown to induce phagocytosis by endothelial cells, a mechanism which is discussed as a potential strategy of C. albicans to escape from the bloodstream (Zink et al., 1996; Phan et al., 2000).”
BackgroundContributions of hyphae and hypha-co-regulated genes to Candida albicans virulence
Kumamoto, C. A., & Vinces, M. D. (2005) · Cellular Microbiology · doi:10.1111/j.1462-5822.2005.00616.x · Cited by 394
“efg1 null mutant cells (lacking a transcription regulator) are extremely defective in damaging HUVEC (endothelial cells) (Phan et al., 2000).”
BackgroundInfluentialCandida albicans dimorphism as a therapeutic target
Jacobsen, I. D., Wilson, D., Wächtler, B., Brunke, S., Naglik, J. R., & Hube, B. (2012) · Expert Review of Anti-infective Therapy · doi:10.1586/eri.11.152 · Cited by 363
Candida albicans Als3, a multifunctional adhesin and invasin
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“For example, they are unable to damage and escape from macrophages (30), and they have markedly reduced capacity to invade and damage both epithelial cells and endothelial cells (43, 45).”
BackgroundSelf-citationFunctional and Structural Diversity in the Als Protein Family of Candida albicans
Sheppard, D. C., Yeaman, M. R., Welch, W. H., Phan, Q. T., Fu, Y., Ibrahim, A. S., Filler, S. G., Zhang, M., Waring, A. J., & Edwards, J. E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401929200 · Cited by 300
Self-citationXu, X.-L., Lee, R. T. H., Fang, H.-M., Wang, Y.-M., Li, R., Zou, H., Zhu, Y., & Wang, Y. (2008) · Cell Host & Microbe · doi:10.1016/j.chom.2008.05.014 · Cited by 289
“The yeast-to-hypha transition facilitates tissue penetration and avoidance of phagocytic destruction in the host (Cutler, 1991; Lo et al., 1997; Phan et al., 2000).”
BackgroundFungal Invasion of Normally Non-Phagocytic Host Cells
Filler, S. G., & Sheppard, D. C. (2006) · PLoS Pathogens · doi:10.1371/journal.ppat.0020129 · Cited by 275
“This process is passive on the part of the organism because killed organisms are able to induce endocytosis similarly to live organisms [27,29].”
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“(32) demonstrated a reduced capacity for efg1 mutants to invade and injure endothelial cells.”
BackgroundFrom commensal to pathogen: stage- and tissue-specific gene expression of Candida albicans.
Hube, B. (2004) · Current Opinion in Microbiology · doi:10.1016/j.mib.2004.06.003 · Cited by 260
Hoefs, S., Mogavero, S., & Hube, B. (2016) · The Journal of Microbiology · doi:10.1007/s12275-016-5514-0 · Cited by 251
“…is a completely passive, host cell-driven process independent of the viability of the Candida cell, active penetration is an active, fungal-driven process mediating penetration of both killed and living host cells (Phan et al., 2000; Park et al., 2005; Dalle et al., 2010; Wächtler et al., 2011).”
BackgroundALTERNATIVECANDIDA ALBICANSLIFESTYLES: Growth on Surfaces
Kumamoto, C. A., & Vinces, M. D. (2005) · Annual Review of Microbiology · doi:10.1146/annurev.micro.59.030804.121034 · Cited by 247
Fungi in endodontic infections
Siqueira, J. F., Jr., & Şen, B. H. (2004) · Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology · doi:10.1016/j.tripleo.2003.12.022 · Cited by 234
Stage‐specific gene expression of Candida albicans in human blood
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“…transition and hydrolytic enzyme secretion, are necessary for penetration of C. albicans through the epithelial and endothelial layers (Hube et al ., 1997; Sanglard et al ., 1997; Ibrahim et al ., 1998; Brown and Gow, 1999; Sundstrom, 1999; Ernst, 2000; Phan et al ., 2000; Felk et al ., 2002).”
BackgroundHost Cell Invasion and Virulence Mediated by Candida albicans Ssa1
Sun, J. N., Solis, N. V., Phan, Q. T., Bajwa, J. S., Kashleva, H., Thompson, A., Liu, Y., Dongari-Bagtzoglou, A., Edgerton, M., & Filler, S. G. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1001181 · Cited by 220
“Therefore, the host cell damage defects of the ssa1D/D mutant were not due to impaired hyphal formation [27,32,33].”
BackgroundMethodInfluentialSelf-citationSalivary mucins in host defense and disease prevention
Frenkel, E. S., & Ribbeck, K. (2015) · Journal of Oral Microbiology · doi:10.3402/jom.v7.29759 · Cited by 209
Park, H., Myers, C. L., Sheppard, D. C., Phan, Q. T., Sanchez, A. A., E. Edwards, J., & Filler, S. G. (2004) · Cellular Microbiology · doi:10.1111/j.1462-5822.2004.00476.x · Cited by 207
“Endocytosis assay The number of organisms that were associated with and endocytosed by FaDu cells was determined using a minor modification of our previously described differential fluorescence assay (Phan et al., 2000; Tsuchimori et al., 2000; Belanger et al., 2002).”
BackgroundMethodResultInfluentialSelf-citationAdaptation to environmental pH in Candida albicans and its relation to pathogenesis
Davis, D. A. (2003) · Current Genetics · doi:10.1007/s00294-003-0415-2 · Cited by 196
“and the C. albicans must then respond to stimulate endothelial cell damage (Mayer et al. 1992; Filler et al. 1995; Phan et al. 2000 ).”
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Brand, A. (2011) · International Journal of Microbiology · doi:10.1155/2012/517529 · Cited by 184
“albicans hyphae are more efficiently endocytosed than yeast cells [58].”
Targeting Candida albicans filamentation for antifungal drug development
Vila, T., Romo, J. A., Pierce, C. G., McHardy, S. F., Saville, S. P., & Lopez-Ribot, J. L. (2017) · Virulence · doi:10.1080/21505594.2016.1197444 · Cited by 174
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“In the human pathogen Candida albicans, the whole-genome microarray has been applied to study drug resistance, cell wall synthesis, and pathogenic development (Andes et al., 2005; Hull et al., 2000; Kadosh and Johnson, 2005; Liu et al., 2005; Phan et al., 2000; Sohn et al., 2003).”
BackgroundEisman, B., Alonso-Monge, R., Román, E., Arana, D., Nombela, C., & Pla, J. (2006) · Eukaryotic Cell · doi:10.1128/ec.5.2.347-358.2006 · Cited by 163
“albicans, the PAK Cla4 protein is a putative transduction element that has been reported to be involved in morphogenesis and virulence in this fungus (28, 41).”
BackgroundD’Auria, F. D., Tecca, M., Strippoli, V., Salvatore, G., Battinelli, L., & Mazzanti, G. (2005) · Medical Mycology · doi:10.1080/13693780400004810 · Cited by 163
How human pathogenic fungi sense and adapt to pH: the link to virulence
Davis, D. A. (2009) · Current Opinion in Microbiology · doi:10.1016/j.mib.2009.05.006 · Cited by 177
“albicans-mediated killing of the host cell [27].”
Pierce, C. G., & Lopez-Ribot, J. L. (2013) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2013.807245 · Cited by 162
“Although yeast cells are probably disseminated more effectively, filamentous forms are better adapted to penetrate and damage tissue, ultimately causing death [43,45,46].”
Nobile, C. J., Solis, N., Myers, C. L., Fay, A. J., Deneault, J.-S., Nantel, A., Mitchell, A. P., & Filler, S. G. (2008) · Cellular Microbiology · doi:10.1111/j.1462-5822.2008.01198.x · Cited by 150
“Effects of RIM101 and NRG1 on C. albicans morphology In several in vitro infection models, host cell damage capacity correlates with C. albicans morphology (Phan et al., 2000; Villar et al., 2004; Park et al., 2005).”
BackgroundSelf-citationModulation of Morphogenesis in Candida albicans by Various Small Molecules
Shareck, J., & Belhumeur, P. (2011) · Eukaryotic Cell · doi:10.1128/ec.05030-11 · Cited by 146
“evade phagocytes (84), to escape from blood vessels (112), and”
BackgroundCandida albicans and Oral Carcinogenesis. A Brief Review
Cosola, M. D., Cazzolla, A. P., Charitos, I. A., Ballini, A., Inchingolo, F., & Santacroce, L. (2021) · Journal of Fungi · doi:10.3390/jof7060476 · Cited by 154
“albicans is the predominant species and is associated with high concentrations of alcohol dehydrogenase enzyme and P53 that suggests a dysplastic potential factor [95].”
BackgroundAspergillus fumigatusMedA governs adherence, host cell interactions and virulence
Gravelat, F. N., Ejzykowicz, D. E., Chiang, L. Y., Chabot, J. C., Urb, M., MacDonald, K., Al-Bader, N., Filler, S. G., & Sheppard, D. C. (2009) · Cellular Microbiology · doi:10.1111/j.1462-5822.2009.01408.x · Cited by 138
“…of morphologic and sexual development often directly regulate the expression of key virulence factors (Lo et al., 1997; Lengeler et al., 2000; Phan et al., 2000; Sonneborn et al., 2000; Bahn and Sundstrom, 2001, Felk et al., 2002; Fu et al., 2002; Garcia-Sanchez et al., 2004; Sanchez et al.,…”
BackgroundSelf-citationCandida albicans internalization by host cells is mediated by a clathrin-dependent mechanism
Moreno-Ruiz, E., Galán-Díez, M., Zhu, W., Fernández-Ruiz, E., d'Enfert, C., Filler, S. G., Cossart, P., & Veiga, E. (2009) · Cellular Microbiology · doi:10.1111/j.1462-5822.2009.01319.x · Cited by 133
“The first steps of this process are driven by the host cell since killed hyphae are internalized as efficiently as live hyphae even though they do not cause host cell damage (Filler et al., 1995; Phan et al., 2000; Park et al., 2005).”
BackgroundSelf-citationAlarco, A., Marcil, A., Chen, J., Suter, B., Thomas, D. Y., & Whiteway, M. S. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.9.5622 · Cited by 130
“albicans in an in vitro mouse endothelial cell model (39).”
BackgroundCandida and invasive candidiasis: back to basics
Lim, C. S. Y., Rosli, R., Seow, H. F., & Chong, P. P. (2011) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-011-1273-3 · Cited by 130
“[89] reported that all of the null mutants had reduced invasion and injury capabilities.”
BackgroundBensen, E. S., Filler, S. G., & Berman, J. G. (2002) · Eukaryotic Cell · doi:10.1128/ec.1.5.787-798.2002 · Cited by 122
“by using the chromium release assay described previously (43).”
BackgroundMethodSelf-citationLinking fungal morphogenesis with virulence
Rooney, P. J., & Klein, B. S. (2002) · Cellular Microbiology · doi:10.1046/j.1462-5822.2002.00179.x · Cited by 122
“The filamentation-deficient efg/efg cph/cph double knockout strain and the constitutively hyphal tup1/tup1 mutant demonstrated a decreased ability to induce endothelial cell injury relative to the parent strain (Phan et al., 2000).”
BackgroundCandida albicansand cancer: Can this yeast induce cancer development or progression?
Ramirez‐Garcia, A., Rementería, A., Urízar, J. M. A., Moragues, M. D., Antoran, A., Pellón, A., Abad, A., & Hernando, F. L. (2014) · Critical Reviews in Microbiology · doi:10.3109/1040841x.2014.913004 · Cited by 128
“…et al., 1995, 1996; Glee et al., 2001; Grubb et al., 2009; Jong et al., 2003; Kurihara et al., 2003; Lim et al., 2011; Mayer et al., 2012; Orozco et al., 2000; Park et al., 2009; Phan et al., 2000;Ramirez-Garcia et al., 2011, 2013; Sanchez et al., 2004; Seidl et al., 2012; Zhao et al., 2007).”
BackgroundAlbano, L., Bretagne, S., Mamzer, M., Kacso, I., Desnos‐Ollivier, M., Guerrini, P., Luong, T. L., Cassuto, É., Dromer, F., Lortholary, O., et al. (2008) · Clinical Infectious Diseases · doi:10.1086/595688 · Cited by 120
Lemar, K. M., Turner, M., & Lloyd, D. (2002) · Journal of Applied Microbiology · doi:10.1046/j.1365-2672.2002.01707.x · Cited by 118
“The morphological forms of C. albicans (Phan et al. 2000) and the physiological state of the host are also considered to be important.”
BackgroundLopes-Bezerra, L. M., & Filler, S. G. (2003) · Blood · doi:10.1182/blood-2003-06-2186 · Cited by 118
Self-citationN-cadherin Mediates Endocytosis of Candida albicans by Endothelial Cells
Phan, Q. T., Fratti, R. A., Prasadarao, N. V., Edwards, J. E., & Filler, S. G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412592200 · Cited by 113
Self-citationDieterich, C., Schandar, M., Noll, M., Johannes, F., Brunner, H., Graeve, T., & Rupp, S. (2002) · Microbiology · doi:10.1099/00221287-148-2-497 · Cited by 113
“This strain, as well as a strain deleted for EFG1, also showed limited abilities to damage endothelial cells (Phan et al., 2000).”
BackgroundResultInfluentialLiu, H. (2002) · International Journal of Medical Microbiology · doi:10.1078/1438-4221-00215 · Cited by 110
Forche, A., Cromie, G., Gerstein, A. C., Solis, N. V., Pisithkul, T., Srifa, W., Jeffery, E., Abbey, D., Filler, S. G., Dudley, A. M., et al. (2018) · Genetics · doi:10.1534/genetics.118.301019 · Cited by 94
“Mutants with filamentation defects cause less damage to epithelial and endothelial cells in vitro (Phan et al. 2000; Tsuchimori et al. 2000; Bensen et al. 2002).”
BackgroundSelf-citationSanchez, A. A., Johnston, D. A., Myers, C., Edwards, J. E., Mitchell, A. P., & Filler, S. G. (2004) · Infection and Immunity · doi:10.1128/iai.72.1.598-601.2004 · Cited by 101
“with endothelial cells isolated from human umbilical cord veins, as described previously (24).”
BackgroundMethodInfluentialSelf-citationImmune Sensing of Candida albicans
Bojang, E., Ghuman, H., Kumwenda, P., & Hall, R. A. (2021) · Journal of Fungi · doi:10.3390/jof7020119 · Cited by 96
Mayer, F. L., Wilson, D., Jacobsen, I. D., Miramón, P., Slesiona, S., Bohovych, I., Brown, A. J. P., & Hube, B. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038584 · Cited by 101
“albicans strains [80,81].”
Urban, C. F., Xiong, X. B., Sohn, K., Schröppel, K., Brunner, H., & Rupp, S. (2005) · Molecular Microbiology · doi:10.1111/j.1365-2958.2005.04771.x · Cited by 101
“…hyphal development, respectively, and are required for virulence both in vivo and in vitro , for morphogenesis and for expression of adhesion proteins of the cell wall in C. albicans (Braun and Johnson, 1997; 2000; Lo et al ., 1997; Phan et al ., 2000; Dieterich et al ., 2002; Sohn et al ., 2003).”
BackgroundMechanisms of Candida albicans Trafficking to the Brain
Liu, Y., Mittal, R., Solis, N. V., Prasadarao, N. V., & Filler, S. G. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002305 · Cited by 93
“HUVECs were harvested from umbilical cords with collagenase and grown in M-199 medium supplemented with 10% fetal bovine serum and 10% defined bovine calf serum (Gemini Bio-Products), and containing 2 mM L-glutamine with penicillin and streptomycin (Irvine Scientific) as previously described [51].”
MethodSelf-citationInvasive Phenotype ofCandida albicansAffects the Host Proinflammatory Response to Infection
Villar, C. C., Kashleva, H., Mitchell, A. P., & Dongari‐Bagtzoglou, A. I. (2005) · Infection and Immunity · doi:10.1128/iai.73.8.4588-4595.2005 · Cited by 89
“Because the proinflammatory response of epithelial (47) or endothelial (38) cells to C.”
BackgroundMaddi, A., Bowman, S. M., & Free, S. J. (2009) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2009.06.005 · Cited by 93
“, 2006), and help in the invasion of host tissues (Phan et al., 2000).”
Grubb, S. E. W., Murdoch, C., Sudbery, P. E., Saville, S. P., Lopez-Ribot, J. L., & Thornhill, M. H. (2008) · Infection and Immunity · doi:10.1128/iai.00332-08 · Cited by 87
“However, it is also possible that yeast forms adhere to the endothelial surface, germinate there, and then penetrate and damage the endothelium during transmigration (22) or that yeast forms adhere and are then endocytosed before germinating within the endothelial cell to cause damage (64).”
BackgroundFrank, C. F., & Hostetter, M. K. (2007) · Translational research · doi:10.1016/j.trsl.2006.11.006 · Cited by 91
New signaling pathways govern the host response to C. albicans infection in various nichesPreprint
Liu, Y., Shetty, A. C., Schwartz, J. A. J., Bradford, L. L., Xu, W., Phan, Q. T., Kumari, P., Mahurkar, A., Mitchell, A. P., Ravel, J., et al. (2015) · Genome Research · doi:10.5281/zenodo.13524844 · Cited by 88
“The observation that invasion-defective C. albicans mutants display attenuated virulence in murine models of OPC and HDC is evidence of the critical importance of invasion to virulence (Phan et al. 2000; Sanchez et al. 2004; Park et al. 2005; Chiang et al. 2007).”
BackgroundSelf-citationCandida albicansactively modulates intracellular membrane trafficking in mouse macrophage phagosomes
Fernández‐Arenas, E., Bleck, C. K. E., Nombela, C., Gil, C., Griffiths, G., & Diez‐Orejas, R. (2008) · Cellular Microbiology · doi:10.1111/j.1462-5822.2008.01274.x · Cited by 91
“In addition, this efg1D/cph1D avirulent mutant offers the possibility to study differences in the host immune response between virulent versus avirulent C. albicans strains (Lo et al., 1997; Phan et al., 2000; Dieterich et al., 2002; Gow et al., 2003; Lu et al., 2006; Chamilos et al., 2007).”
BackgroundClinical Implications of Oral Candidiasis: Host Tissue Damage and Disseminated Bacterial Disease
Kong, E. F., Kucharíková, S., Dijck, P. V., Peters, B. M., Shirtliff, M. E., & Jabra‐Rizk, M. A. (2014) · Infection and Immunity · doi:10.1128/iai.02843-14 · Cited by 84
“hyphae are not capable of causing mucosal infections (44, 46, 48).”
BackgroundKörting, H. C., Hube, B., Oberbauer, S., Januschke, E., Hamm, G., Albrecht, A., Borelli, C., & Schaller, M. (2003) · Journal of Medical Microbiology · doi:10.1099/jmm.0.05125-0 · Cited by 86
“…strains which lacked either functional Efg1, Cph1 or both factors (Brown&Gow, 1999; Stoldt et al., 1997; Bockmuhl & Ernst, 2001; Dieterich et al., 2002; Kohler & Fink, 1996; Leberer et al., 1997; Lo et al., 1997; Sonneborn et al., 1999b;Weide &Ernst, 1999; Lewis et al., 2002; Phan et al., 2000).”
BackgroundMethodInfluentialMartínez-López, R., Park, H., Myers, C., Gil, C., & Filler, S. (2006) · Eukaryotic Cell · doi:10.1128/ec.5.1.140-147.2006 · Cited by 81
“albicans that are endocytosed poorly and cause little damage to endothelial cells and oral epithelial cells have significantly reduced virulence in mouse models of hematogenously disseminated or oropharyngeal candidiasis (20, 21, 25).”
BackgroundSelf-citationLu, Y., Su, C., Mao, X., Raniga, P. P., Liu, H., & Chen, J. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e08-02-0173 · Cited by 82
“albicans with endothelial and epithelia cells, as well as biofilm formation and catheter infection (Lo et al., 1997; Phan et al., 2000; Dieterich et al., 2002; Lewis et al., 2002; Ramage et al., 2002; Garcia-Sanchez et al., 2004).”
BackgroundVendelė, I., Willment, J. A., Silva, L. M., Palma, A. S., Chai, W., Liu, Y., Feizi, T., Spyrou, M., Stappers, M. H. T., Brown, G. D., et al. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1007927 · Cited by 81
Fungal invasion of epithelial cells
Yang, W., Yan, L., Wu, C., Zhao, X., & Tang, J. (2014) · Microbiological Research · doi:10.1016/j.micres.2014.02.013 · Cited by 79
“Fungal-induced ndocytosis is a passive process since killed hyphae are endocyosed as avidly as living hyphae (Phan et al. 2000; Park et al. 2005).”
BackgroundPadmavathi, A. R., Sriyutha Murthy, P., Das, A., Priya, A., Sushmitha, T. J., Pandian, S. K., & Rao, T. S. (2020) · Biofouling · doi:10.1080/08927014.2020.1715371 · Cited by 81
“…phenotypes are virulent parameters that contribute to the invasive behaviour of C. albicans which is quintessential for adhesion and invasion into host epithelial cells (Phan et al. 2000; Zakikhany et al. 2007) and spreading infections to deep seated tissues (Lo et al. 1997; Moyes et al. 2015).”
BackgroundGil-Bona, A., Parra‐Giraldo, C. M., Hernáez, M. L., Reales‐Calderón, J. A., Solis, N. V., Filler, S. G., Monteoliva, L., & Gil, C. (2015) · Journal of Proteomics · doi:10.1016/j.jprot.2015.06.006 · Cited by 80
“albicans strains to the FaDu cell line was measured using a (51)Cr release assay as described previously [45].”
MethodSelf-citationJackson, S., Coulthwaite, L., Loewy, Z. G., Scallan, A., & Verran, J. (2014) · Journal of Prosthetic Dentistry · doi:10.1016/j.prosdent.2014.02.003 · Cited by 77
Inactivation of Kex2p Diminishes the Virulence of Candida albicans
Newport, G., Kuo, A., Flattery, A. M., Gill, C., Blake, J., Kurtz, M. B., Abruzzo, G. K., & Agabian, N. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209713200 · Cited by 79
Spiering, M. J., Moran, G. P., Chauvel, M., MacCallum, D. M., Higgins, J., Hokamp, K., Yeomans, T., d’Enfert, C., Coleman, D. C., & Sullivan, D. J. (2009) · Eukaryotic Cell · doi:10.1128/ec.00291-09 · Cited by 81
“A trait critically important for Candida virulence especially in endothelial and epithelial infection models is the ability to undergo the yeast-to-hypha transition (hyphal morphogenesis) (16, 26, 31).”
BackgroundChiang, L. Y., Sheppard, D. C., Gravelat, F. N., Patterson, T. F., & Filler, S. G. (2008) · Infection and Immunity · doi:10.1128/iai.01510-07 · Cited by 77
“Other fungal pathogens, such as Candida albicans, stimulate endothelial cell expression of these proinflammatory mediators (4, 16, 21).”
BackgroundSelf-citationAn RNA Transport System in Candida albicans Regulates Hyphal Morphology and Invasive Growth
Elson, S. L., Noble, S. M., Solis, N. V., Filler, S. G., & Johnson, A. D. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000664 · Cited by 76
“Endothelial and epithelial cell damage assays were performed as previously described [45,46].”
BackgroundMethodSelf-citationHausauer, D. L., Gerami‐Nejad, M., Kistler-Anderson, C., & Gale, C. A. (2005) · Eukaryotic Cell · doi:10.1128/ec.4.7.1273-1286.2005 · Cited by 75
“albicans strains with defects in hyphal morphogenesis appear to be less virulent in animal and tissue-based models of candidiasis (9, 36, 45, 48), leading to the idea that morphogenesis is required for virulence.”
BackgroundBrand, A., Vacharaksa, A., Bendel, C. M., Norton, J., Haynes, P. R., Henry‐Stanley, M. J., Wells, C. L., Ross, K., Gow, N. A. R., & Gale, C. A. (2008) · Eukaryotic Cell · doi:10.1128/ec.00453-07 · Cited by 73
“The ability to form hyphae strongly correlates with the ability to injure host cells (44), and many of the C.”
BackgroundToenjes, K. A., Munsee, S. M., Ibrahim, A. S., Jeffrey, R., Edwards, J. E., & Johnson, D. I. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.3.963-972.2005 · Cited by 72
“assay in 96-well tissue culture plates described previously (32).”
MethodMogavero, S., Sauer, F. M., Brunke, S., Allert, S., Schulz, D., Wisgott, S., Jablonowski, N., Elshafee, O., Krüger, T., Kniemeyer, O., et al. (2021) · Cellular Microbiology · doi:10.1111/cmi.13378 · Cited by 74
“Als3, which acts as both an adhesin and invasin (Phan et al., 2000; Wachtler et al., 2011).”
BackgroundSpellberg, B. J., Johnston, D. A., Phan, Q. T., Edwards, J. E., French, S. W., Ibrahim, A. S., & Filler, S. G. (2003) · Infection and Immunity · doi:10.1128/iai.71.10.5756-5764.2003 · Cited by 68
“The hyphadeficient mutant strain is defective in its ability to injure host cells in vitro (12, 24), and it is therefore likely that this mutant strain causes less damage to the renal parenchyma and is a weaker stimulus for IL-10 production than the wild-type strain.”
BackgroundSelf-citationFungal Infection of the Radicular Dentin
SIQUEIRAJR, J., Rôças, I. N., LOPES, H., Elias, C. N., & DEUZEDA, M. (2002) · Journal of Endodontics · doi:10.1097/00004770-200211000-00006 · Cited by 67
Adhesion of Candida albicans to Endothelial Cells under Physiological Conditions of Flow
Grubb, S. E. W., Murdoch, C., Sudbery, P. E., Saville, S. P., Lopez-Ribot, J. L., & Thornhill, M. H. (2009) · Infection and Immunity · doi:10.1128/iai.00518-09 · Cited by 66
“Previous in vitro studies showed that yeast forms adhere to the endothelial cell surface before undergoing germination and causing endothelial damage (6, 19).”
BackgroundAspartic proteinases of C andidaspp.: role in pathogenicity and antifungal resistance
Silva, N. C., Nery, J., & Dias, A. L. T. (2013) · Mycoses · doi:10.1111/myc.12095 · Cited by 72
Ura-status-dependent adhesion of Candida albicans mutants
Bain, J. M., Stubberfield, C. R., & Gow, N. A. R. (2001) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2001.tb10905.x · Cited by 63
The Novel Candida albicans Transporter Dur31 Is a Multi-Stage Pathogenicity Factor
Mayer, F. L., Wilson, D., Jacobsen, I. D., Miramón, P., Große, K., & Hube, B. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002592 · Cited by 62
“albicans strains for 15 hours and the degree of oral epithelial cell damage was quantified by measuring lactate dehydrogenase (LDH) activity [29,30].”
BackgroundMethodBernhardt, J., Herman, D., Sheridan, M. J., & Calderone, R. (2001) · The Journal of Infectious Diseases · doi:10.1086/323807 · Cited by 63
Małagocka, J., Grell, M. N., Lange, L., Eilenberg, J., & Jensen, A. B. (2015) · Journal of Invertebrate Pathology · doi:10.1016/j.jip.2015.05.001 · Cited by 60
“Pld1 plays a role in transition from yeast to hyphal type of growth in Candida, a process that is essential for invasion of host cells (Hube et al., 2001; Phan et al., 2000).”
BackgroundRole of Candida albicans polymorphism in interactions with oral epithelial cells
Villar, C. C., Kashleva, H., & Dongari‐Bagtzoglou, A. I. (2004) · Oral Microbiology and Immunology · doi:10.1111/j.1399-302x.2004.00150.x · Cited by 60
Transcriptional Responses of Candida albicans to Epithelial and Endothelial Cells
Park, H., Liu, Y., Solis, N. V., Spotkov, J., Hamaker, J. J., Blankenship, J. R., Yeaman, M. R., Mitchell, A. P., Liu, H., & Filler, S. G. (2009) · Eukaryotic Cell · doi:10.1128/ec.00165-09 · Cited by 59
“Prior studies indicate that mutant germination defects are invariably associated with endothelial cell damage defects (48, 59), so the yck2/yck2 mutant is novel in separating these two phenotypes.”
BackgroundMethodSelf-citationExposure of Candida albicans β (1,3)-glucan is promoted by activation of the Cek1 pathway
Chen, T., Jackson, J. W., Tams, R. N., Davis, S. E., Sparer, T. E., & Reynolds, T. B. (2019) · PLOS Genetics · doi:10.1371/journal.pgen.1007892 · Cited by 56
Candida albicans protein kinase CK2 governs virulence during oropharyngeal candidiasis
Chiang, L. Y., Sheppard, D. C., Bruno, V. M., Mitchell, A. P., Edwards, J. E., & Filler, S. G. (2007) · Cellular Microbiology · doi:10.1111/j.1462-5822.2006.00784.x · Cited by 59
“They were cultured as previously described (Phan et al., 2000) in M-199 medium supplemented with 10% fetal bovine serum and 10% defined bovine calf serum (both from Gemini Bio-Products), and containing 2 mM L-glutamine with penicillin and streptomycin (Irvine Scientific).”
BackgroundMethodInfluentialSelf-citationVonk, A. G., Netea, M. G., van der Meer, J. W. M., & Kullberg, B. J. (2006) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.6.9.891 · Cited by 54
“albicans can escape from the endothelial cell by phagosome fusion with the abluminal plasma membrane, or by damaging the endothelial cell by germination (Figure 1) [18,20,21].”
BackgroundPathogenesis I: interactions of host cells and fungi
Clemons, K. V., Calich, V. L. G., Burger, E., Filler, S. G., Graziuttit, M., Murphy, J. W., Roilides, E., Čampa, A., Dias, M. R., Edwards, J. E., et al. (2000) · Medical Mycology · doi:10.1080/mmy.38.s1.99.111 · Cited by 54
Self-citationZhang, L., Chang, W., Sun, B., Groh, M., Speicher, A., & Lou, H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028953 · Cited by 52
“Studies have demonstrated that filamentation plays a crucial role in the pathogenic process [3,4,5].”
BackgroundTherapeutic Potential of Thiazolidinedione-8 as an Antibiofilm Agent against Candida albicans
Feldman, M., Al-Quntar, A., Polacheck, I., Friedman, M., & Steinberg, D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093225 · Cited by 52
“albicans to evade macrophages [32], escape from blood vessels [33], and colonize medical devices by forming biofilms [9,34].”
BackgroundBertolini, M., Xu, H., Sobue, T., Nobile, C. J., Cury, A. A. D. B., & Dongari‐Bagtzoglou, A. I. (2015) · Molecular Oral Microbiology · doi:10.1111/omi.12095 · Cited by 49
“Germination of fungal cells to form true hyphae is a pre-requisite for epithelial invasion and damage in several experimental systems (Phan et al., 2000; Schlecht et al., 2014; Villar et al., 2004).”
BackgroundLu, Q., Jayatilake, J. A. M. S., Samaranayake, L. P., & Jin, L. (2006) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700346 · Cited by 49
“albicans efg1/efg1 cph1/ cph1 mutant is unable to form hyphae under any conditions and is lowly virulent in animal or cell based systems (Lo et al., 1997; Phan et al., 2000).”
BackgroundResultSohn, K., rek, I. S. ⁄., Fertey, J., Königsdorfer, A., Joffroy, C. M., Hauser, N., Zelt, G., Brunner, H., & Rupp, S. (2006) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2006.00130.x · Cited by 50
Rottmann, M., Dieter, S., Brunner, H., & Rupp, S. (2003) · Molecular Microbiology · doi:10.1046/j.1365-2958.2003.03358.x · Cited by 47
“As the ability to switch between a yeast and a hyphal form is essential for virulence in C. albicans (Lo et al ., 1997; Phan et al ., 2000), the components required for this differentiation could be potential virulence factors.”
BackgroundNisin Z inhibits the growth ofCandida albicansand its transition from blastospore to hyphal form
Lay, C., Akerey, B., Fliss, I., Subirade, M., & Rouabhia, M. (2008) · Journal of Applied Microbiology · doi:10.1111/j.1365-2672.2008.03908.x · Cited by 47
“Host cell invasion and damage are likely critical virulence attributes of C. albicans (Phan et al. 2000; Sanchez et al. 2004; Park et al. 2005; Chiang et al. 2007).”
BackgroundSeman, B. G., Moore, J. L., Scherer, A. K., Blair, B. A., Manandhar, S., Jones, J. M., & Wheeler, R. T. (2018) · Infection and Immunity · doi:10.1128/iai.00415-18 · Cited by 50
vandenBerg, A. L., Ibrahim, A. S., Edwards, J. E., Toenjes, K. A., & Johnson, D. I. (2004) · Eukaryotic Cell · doi:10.1128/ec.3.3.724-734.2004 · Cited by 46
“ously (37), using human umbilical vein ECs incubated for 3 h in the presence of 5 10(5) of C.”
The Swi/Snf chromatin remodeling complex is essential for hyphal development in Candida albicans
Mao, X., Cao, F., Nie, X., Liu, H., & Chen, J. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.04.009 · Cited by 45
The role of diclofenac sodium in the dimorphic transition in Candida albicans
Ghalehnoo, Z. R., Rashki, A., Najimi, M., & Domínguez, Á. (2009) · Microbial Pathogenesis · doi:10.1016/j.micpath.2009.12.003 · Cited by 42
Role of Endothelial Cell Septin 7 in the Endocytosis of Candida albicans
Phan, Q. T., Eng, D. K.-M., Mostowy, S., Park, H., Cossart, P., & Filler, S. G. (2013) · mBio · doi:10.1128/mbio.00542-13 · Cited by 44
Self-citationShareck, J., Nantel, A., & Belhumeur, P. (2011) · Eukaryotic Cell · doi:10.1128/ec.00305-10 · Cited by 41
Metadata
- Authors
- Phan, Q. T., Belanger, P. H., & Filler, S. G.
- Affiliations
- University of California, Los Angeles (US)
- ORCID
- Filler, Scott G.
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2000-06
- Volume
- 68
- Issue
- 6
- Pages
- 3485-3490
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC97632
- OpenAlex
- W2134152581
- Cited by
- 181
- References
- 31
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 2 · 2018: 8 · 2017: 4 · 2016: 4 · 2015: 6 · 2014: 13 · 2013: 7 · 2012: 7
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Infection and Immunity (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Burroughs Wellcome Fund
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (P01 AI-37194, R29AI040636, R01AI019990, R01-AI19990, P01AI037194)
- National Center for Research Resources (M01RR000425)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
- Keywords
- Candida albicans, hyphal development, filamentation, endothelial cells, pseudohyphae, endothelial cell invasion, leukocyte adhesion molecules, E-selectin, ICAM-1, inflammation, virulence, yeast-to-hypha transition
- MeSH terms
- Candida albicans, DNA-Binding Proteins, Endocytosis, Endothelium, Vascular, Fungal Proteins, Genes, Fungal, Humans, Morphogenesis, Mutation, Nuclear Proteins, Repressor Proteins, Transcription Factors, Protein Serine-Threonine Kinases, Intercellular Adhesion Molecule-1, E-Selectin, Saccharomyces cerevisiae Proteins
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