|Year : 2017 | Volume
| Issue : 1 | Page : 82-86
Phenotypic switch: The enigmatic white-gray-opaque transition system of Candida albicans
Sushma Basavaraj Bommanavar1, Sachin Gugwad2, Neelima Malik3
1 Department of Oral Pathology and Microbiology and Forensic Odontology, School of Dental Sciences, Krishna Institute of Medical Sciences, Karad, Maharashtra, India
2 Department of Pedodontics and Preventive Dentistry, School of Dental Sciences, Krishna Institute of Medical Sciences, Karad, Maharashtra, India
3 Department of Oral and Maxillofacial Surgery, School of Dental Sciences, Krishna Institute of Medical Sciences, Karad, Maharashtra, India
|Date of Submission||11-Apr-2015|
|Date of Acceptance||30-Nov-2016|
|Date of Web Publication||5-Apr-2017|
Sushma Basavaraj Bommanavar
Department of Oral and Maxillofacial Pathology, School of Dental Sciences, Krishna Institute of Dental College and Hospital, Karad, Maharastra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Candida albicans represents the most common commensal and opportunistic fungal pathogen colonizing humans. As a member of the normal microflora, it is present on the skin and the mucous membranes of the upper respiratory tract, gastrointestinal tract and female genital tracts. It is therefore not transmitted. It lies in wait for a change in some aspect of the host physiology that normally suppress growth and invasiveness through an enigmatic phenomenon called Phenotypic Switch System or White-Opaque Transition. This system involves reversible and heritable switching between alternative cellular phenotypes. White–opaque switching in Candida albicans was first discovered in 1987. This was initially identified in strain WO-1. Switching has been demonstrated to occur at sites of infection and to occur between recurrent episodes of infection in select cases esp. AIDS and diabetes.
Keywords: Candida albicans, opaque cells, phenotype, phenotypic switch system, white cells
|How to cite this article:|
Bommanavar SB, Gugwad S, Malik N. Phenotypic switch: The enigmatic white-gray-opaque transition system of Candida albicans. J Oral Maxillofac Pathol 2017;21:82-6
|How to cite this URL:|
Bommanavar SB, Gugwad S, Malik N. Phenotypic switch: The enigmatic white-gray-opaque transition system of Candida albicans. J Oral Maxillofac Pathol [serial online] 2017 [cited 2022 Aug 11];21:82-6. Available from: https://www.jomfp.in/text.asp?2017/21/1/82/203781
| Introduction|| |
Candida albicans represents the most permeative fungal pathogen colonizing humans. C. albicans is an unicellular yeast of the Cryptococcaceae family with a single bud. As a member of the normal microflora, it is present on the skin and the mucous membranes of the upper respiratory tract, gastrointestinal tract and female genital tracts. It is, therefore, not transmitted. It reproduces by asexual budding and grows rapidly at 25–37°C and within a pH range of 2–8. There are several medically important Candida species, of which C. albicans, Candida tropicalis, Candida glabrata, Candida parapsilosis and Candida krusei are the most frequently isolated. Among these, C. albicans is the far most common species present in health and disease.,,
C albicans exists in two forms – pseudohyphae and yeast forms – a trait known as dimorphism (grows as either yeast or hyphal cells). The yeast form is believed to be innocuous, but the hyphae form is usually associated with invasion into the host tissue. The hyphae are approximately 2 μm in diameter and showed a large population of mitochondria localized at the tip region. This organization is due to large energy required for hyphae extension. This transition from a benign yeast type to highly invasive hyphae type depends on changes in the host defenses, i.e., elude the immune system by altering the surface antigens and on environmental signals that allow it to express pathogenic factors which are normally repressed including changes in the fungal response to antifungal agents.
The factors involved its pathogenicity are – mannoprotein component, i.e., the extracellular polymeric material that coats the surface of C. albicans plays a role in adherence. Second, C. albicans produces a range of proteinases and phospholipases which are particularly concentrated on the tips of the fungal hyphae that disrupts the cell membrane and results in invasion of the pathogen into host tissue. Third, to be a successful pathogen, C. albicans has developed the capacity to vary phenotype by spontaneously generating variants within infecting populations. This empirical axiomatic phenomenon is called as Phenotypic Switching System. It is also known as phenotypic plasticity or bistable switching system (white to opaque) or tristable (white to gray to opaque) switching system.
| What Is Phenotypic Switching: Evolution Of It'S Terminology|| |
Phenotypic switching is defined as “an in vitro reversible phenomenon with spontaneous emergence of colonies with altered colony morphology at rates higher than somatic mutation rates.”, This insidious strategy allows them to undergo rapid adaptation in response to environmental challenges such as individual body locations that may exhibit drastic differences in temperature and pH. The ability to grow in different morphological forms is critical for both its commensal lifestyle and its existence as a pathogen.,,
The ''white-opaque'' transition is a well-known bistable phenotypic switching system in C. albicans. Recently, it has been observed that an intermediate phase between the white and opaque phenotypes does exist and proposed that the phenotypic switching system in this species may be tristable; the so-called ''white-gray-opaque'' tristable phenotypic switching system in C. albicans as illustrated in [Figure 1]. Switching can also be seen in C. glabrata and Candida neoformans. Switching has been demonstrated to occur at sites of infection and between recurrent episodes of infection in selected cases, especially AIDS and diabetes.
|Figure 1: Diagrammatic illustration of phenotypic switch system with its terminology|
Click here to view
| Phenotypic Switching In Candida Albicans And It'S Historical Background|| |
C. albicans is a commensal that colonizes the human host in various niches. Three different switching systems were first described by Soll et al., The first candida model switching strain, 3153A switching system, discovered in 1985, demonstrated that common strains of C. albicans switched reversibly between a number of variant phenotypes, that were quite heterogeneous and produced at least seven different phenotypes including “original smooth,” “star,” “irregular wrinkle,” “ring,” “mottled,” “fuzzy,” and “revertant smooth.”,, Another system included strains that switch between colonies with and without dense myceliation. Finally, the classically studied strain is white-opaque switching, first discovered in 1987 was isolated from the bloodstream of a bone marrow transplant patient at The University of Iowa Hospitals and Clinics. This strain consists of two phases, one that grows as smooth white colonies called the white cells and one that is rod-like and grows as flat gray colonies called the opaque cells.
In yesteryears, most research has been performed on the white-opaque switching strain. A novel morphological phenotype of C. albicans, referred to as the ''gray'' phenotype was identified. This phenotype is heritable, but distinct from the previously identified white and opaque phenotypes in cellular and colony appearance, global gene expression profiles, secreted aspartyl proteinase (SAP) activities and virulence characteristics. The gray phenotype, together with the white and opaque phenotypes, forms a novel tristable and heritable switching system in C. albicans.
The various distinguishing features between white and opaque cells are as follows:
- White cells are round with smooth, domed colonies, whereas opaque cells are bean-shaped, flatter with translucent colonies,
- The interaction of white and opaque cells with the immune system also differs, i.e., white cells secrete a chemoattractant for leukocytes, whereas opaque cells do not. In addition, white and opaque cells are phagocytosed by macrophages, suggesting that white-opaque switching may be an adaptive mechanism to favor C. albicans cells escape the host immune system
- Opaque cells differed from white cells in their sensitivity to neutrophils and reactive oxygen species, adhesion to human cells and plastics, secretion of proteinases and resistance to antifungals
- One of the most fascinating differences observed between white and opaque cells was the expression of genes involved in glucose metabolism. White cells specially expressed genes involved in fermentative metabolism, whereas opaque cells expressed genes involved in oxidative metabolism. This difference occurred under both aerobic and anaerobic conditions
- White and opaque cells also differ in their gene expression profiles, mating competency and virulence characteristics., Opaque cells can mate more efficiently and are better at cutaneous infections than white cells, whereas white cells are more virulent in systemic candidiasis., as illustrated in [Figure 2] and [Figure 3].
|Figure 2: Photomicrograph of white hemispherical colony morphology referred to as the “white phase and a grey flat colony morphology, referred to as the “opaque phase as shown from (a-g). (Courtesy : Judith Berman and Peter E. Sudbery Candida albicans: A molecular revolution built on lessons from budding yeast. Nature Reviews Genetics 3, 918-932 ; December 2002)|
Click here to view
|Figure 3: Photomicrograph of white cells phase and opaque cells. (Courtesy: Judith Berman and Peter E. Sudbery Candida albicans: A molecular revolution built on lessons from budding yeast. Nature Reviews Genetics 3, 918-932; December 2002)|
Click here to view
| Molecular Pathogenesis Of Switching System|| |
Antigenic variation, a common adaptive strategy of microbial pathogens, is mechanisms used by these pathogens to stochastically change their cell surface composition. Strains of C. albicans, the most important fungal pathogen of humans, are able to spontaneously and reversibly switch phenotypes that affects the size and shape of cells, their ability to form hyphae, their surface properties of adhesion and permeability, membrane composition, range of secretory products, sensitivity to neutrophils and oxidants, antigenicity and drug susceptibility. These traits are transcriptionally controlled by expression of various genes such as SAP genes SAP1 and SAP3,,,,, a glucose-lipid-regulated protein gene WH11,, membrane protein gene OP4, two component regulator gene CaNIK1, transcription factor gene EFG1 and a transporter gene CDR3. Studies using high-density oligonucleotide microarray analysis to profile global gene expression ratified that these genes were associated with wide range of functional identification that inferred metabolic preferences and concluded that switching extends beyond antigenic variation to include metabolic pathways, which itself may reflect inherent differences in the efficiency with which each switch phenotype is able to exploit available nutrients and adapt to ambient conditions. For example, opaque cells expressed a transcriptional profile consistent with oxidative metabolism and white cells expressed a fermentative one. Furthermore, the virulence of W- and O-cells depends on the site of infection; W-cells were more virulent in disseminated infections and O-cells were more virulent in cutaneous ones, which is consistent with the availability of glucose in the bloodstream and interstitial spaces, but its absence in the skin. This bias was obtained regardless of carbon source, suggesting a connection between phenotypic switching and metabolic flexibility, where metabolic specialization of switch phenotypes enhances selection in relation to the nutrients available at different anatomical sites.
| Host Pathogen Interaction|| |
C. albicans is a communistic microorganism, in which phenotypic switching play an important role in the biology of C. albicans and in the interactions of this fungus with its host. In response to various environmental signals, C. albicans changes its growth mode from the budding yeast form to filamentous growth, which facilitates tissue invasion. The various strains of C. albicans as described previously are homozygous at the mating type locus (MTL) and can spontaneously and reversibly switch from the normal yeast morphology (white) to an elongated cell type (opaque), which is the mating-competent form of the fungus. This influences the ability of C. albicans to colonize and proliferate in specific host niches and its susceptibility to host defense mechanisms. It is currently not understood why C. albicans has integrated a morphological switch into its life cycle to undergo sexual development. C. albicans cells that have become homozygous for the MTL first have to switch from the normal yeast morphology to the opaque cell form to become mating competent., This again is influenced by various environmental signals,, and once these signals are dominated, the switch is turn on and causes superficial infections of skin, mucosa as well as life-treating disseminated infections, especially in immunocompromised individuals.
As we all know in humans, the two important cells that act as the first line of defense in innate immunity are the neutrophils and the dendritic cells. Earlier work by eminent researchers has shown that opaque cells do not readily undergo filamentation under most conditions that promote hyphal formation in white cells, which may result in a reduced ability to invade tissues. Geiger et al. in his study showed that opaque cells do not produce a chemoattractant for neutrophils that is secreted by white cells pointed to the possibility that opaque cells can also avoid detection by these important first-line host defense cells. Kolotila and Diamond hypothesized that opaque cells are in fact more susceptible than white cells to killing by neutrophils and also stimulate the production of reactive oxygen species, which is one mechanism by which these phagocytes destroy invading pathogens, more strongly than do white cells.
Soloviev et al., in 2007, said that there was another attractive candidate, the pH-regulated antigen Pra1, which is predominantly expressed in a highly glycosylated form on the surface of C. albicans hyphae, but not yeast cells and bound by the αmβ2 receptor on PMNs. Pra1 also acts as a chemoattractant for PMNs, and deletion of PRA1 decreased PMN migration and PMN adhesion to and killing of C. albicans. In 2011, he also reported that dendritic cells can recognize C. albicans by an αmβ2 independent mechanism, which would explain our finding that dendritic cells phagocytosed opaque cells under conditions, in which they were not attacked by neutrophils. Dwivedi et al.,, in 2011, concluded that the hyphae express many other cell surface proteins that are not found on yeast cells. One of these, Hyr1, confers even increased resistance to killing by neutrophils and other phagocytes. Hence, by ratification of various studies, this conflicting bias remains to be established to know which hypha-specific antigens and corresponding receptors on neutrophils are responsible for the selective phagocytosis of germinating C. albicans.
| Conclusion|| |
Understanding the regulatory mechanisms of phenotypic switching system will provide insights into several fundamental questions such as how pathogens adapt to the host and survive and propagate under diverse niches. This treatise review explores phenotypic switching in the most common pathogenic fungi, C. albicans and describes the various traits involved, molecular pathogenesis of this switching system and its role in immune cells.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Soll DR, Lockhart SR, Zhao R. Relationship between switching and mating in Candida albicans
. Eukaryot Cell 2003;2:390-7.
Singh A, Verma R, Murari A, Agrawal A. Oral candidiasis: An overview. J Oral Maxillofac Pathol 2014;18 Suppl 1:S81-5.
Prasanna KR. Oral candidiasis – A review. Scholarly J Med 2012;2:6-30.
Dangi YS, Soni MS, Namdeo KP. Oral candidiasis: A review. Int J Pharm Pharm Sci 2010;2:36-41.
Lehmann PF. Fungal structure and morphology. Med Mycol 1998;4:57-8.
Tao L, Du H, Guan G, Dai Y, Nobile CJ, Liang W, et al.
Discovery of a “white-gray-opaque” tristable phenotypic switching system in Candida albicans
: Roles of non-genetic diversity in host adaptation. PLoS Biol 2014;12:e1001830.
Jain N, Hasan F, Fries BC. Phenotypic switching in fungi. Curr Fungal Infect Rep 2008;2:180-8.
Soll DR. High-frequency switching in Candida albicans
. Clin Microbiol Rev 1992;5:183-203.
Whiteway M, Bachewich C. Morphogenesis in Candida albicans
. Annu Rev Microbiol 2007;61:529-53.
Pande K, Chen C, Noble SM. Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans
commensalism. Nat Genet 2013;45:1088-91.
Slutsky B, Staebell M, Anderson J, Risen L, Pfaller M, Soll DR. “White-opaque transition”: A second high-frequency switching system in Candida albicans
. J Bacteriol 1987;169:189-97.
Xie J, Du H, Guan G, Tong Y, Kourkoumpetis TK, Zhang L, et al.
N-acetylglucosamine induces white-to-opaque switching and mating in Candida tropicalis
, providing new insights into adaptation and fungal sexual evolution. Eukaryot Cell 2012;11:773-82.
Lachke SA, Joly S, Daniels K, Soll DR. Phenotypic switching and filamentation in Candida glabrata
. Microbiology 2002;148(Pt 9):2661-74.
Soll DR, Langtimm CJ, McDowell J, Hicks J, Galask R. High-frequency switching in Candida
strains isolated from vaginitis patients. J Clin Microbiol 1987;25:1611-22.
Soll DR. Molecular biology of Candida
pathogenesis. In: Kirsch DR, Kelly R, Kurtz MB, editors. The Genetics of Candida
. Boca Raton, FL: CRC Press; 1990. p. 147-76.
Slutsky B, Buffo J, Soll DR. High-frequency switching of colony morphology in Candida albicans
. Science 1985;230:666-9.
Pomés R, Gil C, Nombela C. Genetic analysis of Candida albicans
morphological mutants. J Gen Microbiol 1985;131:2107-13.
Ramsey H, Morrow B, Soll DR. An increase in switching frequency correlates with an increase in recombination of the ribosomal chromosomes of Candida albicans
strain 3153A. Microbiology 1994;140(Pt 7):1525-31.
Soll DR. Why does Candida albicans
switch? FEMS Yeast Res 2009;9:973-89.
Anderson JM, Soll DR. Unique phenotype of opaque cells in the white-opaque transition of Candida albicans
. J Bacteriol 1987;169:5579-88.
Alby K, Bennett RJ. Stress-induced phenotypic switching in Candida albicans
. Mol Biol Cell 2009;20:3178-91.
Miller MG, Johnson AD. White-opaque switching in Candida albicans
is controlled by mating-type locus homeodomain proteins and allows efficient mating. Cell 2002;110:293-302.
Bennett RJ, Johnson AD. Mating in Candida albicans
and the search for a sexual cycle. Annu Rev Microbiol 2005;59:233-55.
Hube B, Monod M, Schofield DA, Brown AJ, Gow NA. Expression of seven members of the gene family encoding secretory aspartyl proteinases in Candida albicans
. Mol Microbiol 1994;14:87-99.
Morrow B, Srikantha T, Soll DR. Transcription of the gene for a pepsinogen, PEP1, is regulated by white-opaque switching in Candida albicans
. Mol Cell Biol 1992;12:2997-3005.
Morrow B, Srikantha T, Anderson J, Soll DR. Coordinate regulation of two opaque-phase-specific genes during white-opaque switching in Candida albicans
. Infect Immun 1993;61:1823-8.
Morrow B, Ramsey H, Soll DR. Regulation of phase-specific genes in the more general switching system of Candida albicans
strain 3153A. J Med Vet Mycol 1994;32:287-94.
White TC, Miyasaki SH, Agabian N. Three distinct secreted aspartyl proteinases in Candida albicans
. J Bacteriol 1993;175:6126-33.
Kvaal CA, Srikantha T, Soll DR. Misexpression of the white-phase-specific gene WH11 in the opaque phase of Candida albicans
affects switching and virulence. Infect Immun 1997;65:4468-75.
Srikantha T, Soll DR. A white-specific gene in the white-opaque switching system of Candida albicans
. Gene 1993;131:53-60.
Srikantha T, Tsai L, Daniels K, Enger L, Highley K, Soll DR. The two-component hybrid kinase regulator CaNIK1 of Candida albicans
. Microbiology 1998;144(Pt 10):2715-29.
Sonneborn A, Tebarth B, Ernst JF. Control of white-opaque phenotypic switching in Candida albicans
by the Efg1p morphogenetic regulator. Infect Immun 1999;67:4655-60.
Srikantha T, Tsai LK, Daniels K, Soll DR. EFG1 null mutants of Candida albicans
switch but cannot express the complete phenotype of white-phase budding cells. J Bacteriol 2000;182:1580-91.
Kvaal C, Lachke SA, Srikantha T, Daniels K, McCoy J, Soll DR. Misexpression of the opaque-phase-specific gene PEP1 (SAP1) in the white phase of Candida albicans
confers increased virulence in a mouse model of cutaneous infection. Infect Immun 1999;67:6652-62.
Kumamoto CA, Vinces MD. Contributions of hyphae and hypha-co-regulated genes to Candida albicans
virulence. Cell Microbiol 2005;7:1546-54.
Johnson A. The biology of mating in Candida albicans
. Nat Rev Microbiol 2003;1:106-16.
Huang G, Srikantha T, Sahni N, Yi S, Soll DR. CO(2) regulates white-to-opaque switching in Candida albicans
. Curr Biol 2009;19:330-4.
Anderson J, Cundiff L, Schnars B, Gao MX, Mackenzie I, Soll DR. Hypha formation in the white-opaque transition of Candida albicans
. Infect Immun 1989;57:458-67.
Geiger J, Wessels D, Lockhart SR, Soll DR. Release of a potent polymorphonuclear leukocyte chemoattractant is regulated by white-opaque switching in Candida albicans
. Infect Immun 2004;72:667-77.
Kolotila MP, Diamond RD. Effects of neutrophils and in vitro
oxidants on survival and phenotypic switching of Candida albicans
WO-1. Infect Immun 1990;58:1174-9.
Soloviev DA, Fonzi WA, Sentandreu R, Pluskota E, Forsyth CB, Yadav S, et al.
Identification of pH-regulated antigen 1 released from Candida albicans
as the major ligand for leukocyte integrin alphaMbeta2. J Immunol 2007;178:2038-46.
Dwivedi P, Thompson A, Xie Z, Kashleva H, Ganguly S, Mitchell AP, et al.
Role of Bcr1-activated genes Hwp1 and Hyr1 in Candida albicans
oral mucosal biofilms and neutrophil evasion. PLoS One 2011;6:e16218.
Luo G, Ibrahim AS, Spellberg B, Nobile CJ, Mitchell AP, Fu Y. Candida albicans
Hyr1p confers resistance to neutrophil killing and is a potential vaccine target. J Infect Dis 2010;201:1718-28.
[Figure 1], [Figure 2], [Figure 3]
|This article has been cited by|
||The rise in cases of mucormycosis, candidiasis and aspergillosis amidst COVID19
| ||Asmita Ghosh, Anusua Sarkar, Pubali Paul, Parth Patel |
| ||Fungal Biology Reviews. 2021; 38: 67 |
|[Pubmed] | [DOI]|
||Virulence of “white-gray-opaque” tri-stable transformation in clinical Candida albicans in vitro and in vivo
| ||Jing Yang, Wenli Feng, Zhiqin Xi, Lu Yang, Xiaoxia Zhao, Yan Ma, Yanping Ma |
| ||Microbial Pathogenesis. 2021; 154: 104825 |
|[Pubmed] | [DOI]|
||Antifungal Properties of Essential Oils and Their Compounds for Application in Skin Fungal Infections: Conventional and Nonconventional Approaches
| ||Aswir Abd Rashed, Devi-Nair Gunasegavan Rathi, Nor Atikah Husna Ahmad Nasir, Ahmad Zuhairi Abd Rahman |
| ||Molecules. 2021; 26(4): 1093 |
|[Pubmed] | [DOI]|
||Mechanism of Candida pathogenesis: revisiting the vital drivers
| ||Ifeanyi Elibe Mba, Emeka Innocent Nweze |
| ||European Journal of Clinical Microbiology & Infectious Diseases. 2020; 39(10): 1797 |
|[Pubmed] | [DOI]|
||Chromatin Structure and Drug Resistance in Candida spp.
| ||Callum J. O’Kane, Rachel Weild, Edel M. Hyland |
| ||Journal of Fungi. 2020; 6(3): 121 |
|[Pubmed] | [DOI]|
||Cellular plasticity of pathogenic fungi during infection
| ||Kenya E. Fernandes, Dee A. Carter, Mary Ann Jabra-Rizk |
| ||PLOS Pathogens. 2020; 16(6): e1008571 |
|[Pubmed] | [DOI]|
||Candida sp. Infections in Patients with Diabetes Mellitus
| ||Célia Rodrigues, Maria Rodrigues, Mariana Henriques |
| ||Journal of Clinical Medicine. 2019; 8(1): 76 |
|[Pubmed] | [DOI]|