INTRODUCTION — Candidiasis refers to the range of infections caused by species of the fungal genus Candida; these infections can be acute or chronic, localized or systemic. Disseminated candidiasis is life threatening. The great majority of candidiasis is caused by Candida albicans. C. albicans is a common commensal organism in the oropharyngeal cavity, gastrointestinal tract, and vagina of humans but is capable of causing opportunistic infection following disruption of the normal flora, a breach of the mucocutaneous barrier, or a defect in host cellular immunity. C. albicans can be detected as normal microbiota in about 50 percent of individuals [1].
The basic mycology and pathogenesis of candidiasis will be reviewed here. An overview of Candida infections and the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of candidemia and invasive candidiasis are presented separately; other forms of candidiasis are also discussed elsewhere. (See "Overview of Candida infections" and "Candidemia in adults: Epidemiology, microbiology, and pathogenesis" and "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Management of candidemia and invasive candidiasis in adults".)
MYCOLOGY — The genus Candida encompasses about 200 species [2]. They can be found among humans and other mammals, birds, insects, arthropods, fish, animal waste, plants, mushrooms, naturally occurring high-sugar substrates (eg, honey, nectar, grapes) and fermentation products, dairy products, soil, freshwater, seawater, and on airborne particles [3-5].
Infection in humans was first described as oral thrush by Hippocrates in the fifth century BC. In 1853, Charles Robin microscopically observed budding cells and filaments in epithelial scrapings, and he named the fungus Oidium albicans. Subsequently, more than 160 synonyms, including Monilia albicans, were used before Candida albicans became the accepted name for the species.
At least 30 Candida species have caused infection in humans [2]. The most common of these are C. albicans, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis. C. parapsilosis has been recognized as a heterogeneous species, and it was proposed that it be split into three morphologically and physiologically indistinguishable species: C. parapsilosis, C. metapsilosis, and C. orthopsilosis [6]. Phylogenetic analyses show that C. glabrata is more closely related to Saccharomyces cerevisiae than to the C. albicans group [7-9], and future taxonomic revision is possible.
In 1995, Candida dubliniensis was described as a new species to accommodate a subset of isolates previously identified as C. albicans [10]. C. dubliniensis is seen primarily among HIV-infected patients [11]. An environmental source for this species may be the digestive tract of marine birds [5]. There is no clear clinical or experimental evidence that significant pathogenicity differences exist between C. albicans and C. dubliniensis [12], and it is not necessary to routinely distinguish C. dubliniensis from C. albicans in the clinical laboratory [13].
Candida auris was described as a new species after it was detected from a patient in Japan in 2009. Since then, cases have been reported from around the world including much of the United States [14]. C. auris is of particular concern because isolates cause serious infections, are often multidrug resistant, can be associated with outbreaks in health care facilities, and can be misidentified. C. auris infection was designated as a nationally notifiable disease in the United States in 2018. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis", section on 'C. auris emergence'.)
All of the clinically common Candida species are diploid, except for the haploid C. glabrata and C. krusei. Of the aforementioned species, only C. krusei has been determined to have a classic heterothallic sexual cycle [15]. However, mating and genetic recombination does occur in C. albicans and C. tropicalis through a parasexual cycle [9,16-18]. An apparently similar mating mechanism exists in C. dubliniensis, and interspecific mating occurs between C. albicans and C. dubliniensis [19].
Sequencing of the C. albicans genome has demonstrated that this species possesses 6419 genes contained in 8 chromosomes [20]. These data will facilitate proteomic studies, which in turn could lead to better understanding of key biological characteristics of these species, including pathogen-host interactions, improved diagnostics, antifungal drug resistance, novel molecular targets for antifungal therapy, biofilm formation and dynamics, cell signaling, and responses to stress, nutrients, temperature, and pH [21,22].
Growth, morphology, and pleomorphism — Unlike the so-called systemic dimorphic fungi (eg, Histoplasma capsulatum), the morphology of a given Candida species is fundamentally the same whether observed in vitro or in vivo [23]. C. glabrata grows as a small, elliptical, unicellular budding yeast at all times (picture 1). Rarely, buds of C. glabrata can adhere to one another in rudimentary short chains. In marked contrast, C. albicans, C. krusei, C. parapsilosis, and C. tropicalis form elliptical budding cells that typically are larger than those of C. glabrata; they can also form elaborate and well-developed multicellular filaments (picture 2), particularly when in contact with a solid substrate, such as human tissue or agar culture media.
C. krusei and C. parapsilosis can be considered dimorphic because they exhibit budding and pseudohyphal forms. C. albicans and C. tropicalis can form true hyphae (in addition to buds and pseudohyphae) and thus can be considered pleomorphic. Each of these species is capable of exhibiting budding and/or filamentous morphologies in infected tissue.
Usually, the presence of budding yeast and filaments in infected tissue is indicative of candidiasis. However, similar morphologies occur in infections caused by certain opportunistic molds (eg, Purpureocillium lilacinum [formerly Paecilomyces lilacinus]). These mold infections can be histopathologically misdiagnosed as candidiasis if histology is the sole diagnostic criterion used [24-26]. Correlation of histologic and culture results is recommended.
Pseudohyphae and hyphae — Pseudohyphae are morphologically and ontogenically distinct from hyphae. They are formed when buds remain attached to each other and subsequently elongate via differential rates of wall synthesis at various points along the cell wall. Elongation then stops and each terminal cell produces a new apical bud, which elongates in turn. This repeated process of budding and elongation can result in extensive filamentation [27]. Side branches initiate as buds and develop in the same manner. A constriction typically remains and can be seen at the origin of each bud (picture 3). The branching process is regulated in part by a vacuolar protein [28] and by calcineurin [29].
In contrast, true hyphae elongate by a polarized growth process of apical synthesis that does not involve budding. Buds are not present at the hyphal tips; as a result, true hyphae do not exhibit the periodic constrictions that characterize pseudohyphae (picture 4) [30]. C. albicans hyphae have been shown to contain the Spitzenkörper, a vesicle-laden, actin-rich structure, well known in molds, that correlates with tip growth rate and direction [31]. Hyphae develop by a process that is fundamentally different from that of pseudohyphal growth.
Septa — Septa form by centripetal synthesis from the interior of the cell wall inward toward the center of the cell and are present in pseudohyphae, hyphae, and between mature bud cells [30]. The septa provide internal support of the tubular filaments, and a central pore in each septum assures cytoplasmic continuity between cells [30].
White-opaque switching — In addition to yeast, pseudohyphal, and hyphal forms, C. albicans exhibits additional phenotypes of white and opaque colonies. The two phases differ in virulence and gene expression, and reversible switching between phenotypes occurs at a known frequency although the extent to which environmental (including host) stimuli influence switching is not fully known [32,33]. For mating to occur, white cells must first switch to the opaque form. Opaque-phase cells are prevalent as skin colonizers and are less frequently phagocytized by neutrophils in vitro, whereas white-phase cells are more commonly associated with candidemia and are preferentially phagocytized once germ tubes begin to form [34-38].
Genetic control — Signals that trigger each of the growth forms gradually are becoming better understood [39]. Signals include pH, temperature, carbon and nitrogen availability, oxygenation, serum, hormones, and density of the Candida cells within the infected host [40]. For example, one of the key factors, as indicated by studies of C. albicans, is pH of the microenvironment [41-43]. Several pH-regulated genes involved in growth and morphology have been identified: PHR1 is expressed when the ambient pH is 5.5 or higher and correlates with filamentous growth, whereas PHR2 is expressed when the ambient pH is lower than 5.5 (as in the vagina) and correlates with yeast-like growth [41]. Thus, the importance of these genes might vary according to the site of infection. For example, a null mutant of PHR1 was avirulent in a mouse model of systemic infection (the systemic pH being well above 5.5) but maintained its ability to produce vaginal infection (where the pH is approximately 4.5). Conversely, a PHR2 null mutant was able to cause systemic but not vaginal infection [44]. Mutants without Phr1p, a protein product of the PHR1 gene, also lack cross-linking activity associated with the cell wall glucan when grown at pH 8 [45]. Adaptation of C. albicans to the neutral-alkaline environment of the human body by pH sensing is determined mainly by the RIM 101 signal transduction pathway [46].
Several other genes have been identified that regulate the switch from the budding yeast to the filamentous form. Double mutants of EFG1 and CPH1 were nonfilamentous (ie, locked in the yeast form) and unable to form hyphae or pseudohyphae in response to stimuli, such as serum and macrophages [47]. Heat-shock protein 90 (Hsp90), a repressor of hyphal development, can be partially compromised at 30ºC, thus allowing hyphal initiation [48]. Several dozen genes have been shown to contribute to biofilm formation by C. albicans, and a role for quorum-sensing molecules has been postulated as well [43,49-52].
The gene EFG1 encodes a protein Efg1 that contains conserved regions with homology to the human Myc protein; Efg1 appears to activate pseudohyphal formation and downregulate hyphal development [53,54]. In one study of C. albicans, the gene CaRSR1, a RAS-related gene, was necessary for budding and also contributed to germ-tube emergence and cell elongation, which is part of the process of hyphal formation [55]. Alterations in the gene led to decreased virulence. G1 cyclins CLN1, CLN2, and CLN3 have been shown to play a key role in bud formation and regulation of yeast-hyphal transition [56,57]. Various protein kinases in the Cdc2 subfamily also have been shown to regulate filamentous growth [58]. Tor1 is required for contact-dependent induction of C. albicans filaments on artificial surfaces and could be required in vivo as well [59]. A role for quorum sensing as a signaling mechanism for hyphal development has also been suggested [60-63].
Both budding and filamentous forms presumably play a role in the progression of infection in humans [24,25,64]. The ongoing formation and detachment of unicellular buds can facilitate hematogenous dissemination of the yeast following angioinvasion. In contrast, filamentation enhances the ability of Candida species to invade solid tissue via a burrowing process [53]. Nonfilamentous C. albicans can be avirulent [65]. Some investigators have suggested that the hyphae of C. albicans invade epithelial cells using thigmotropism (movement based upon touch) [60,66]. Others argue that chemotropism plays a more important role [67].
Detection in the microbiology laboratory — Candida species can be expected to appear in culture within one to two days in most cases. C. glabrata is an exception; it may take several days to grow.
Definitive identification of yeast isolates traditionally has been based on a combination of morphologic features and physiologic testing. For example, rapid presumptive identification of C. albicans can be accomplished by observing formation of germ tubes (the initiation of true hyphal growth) when incubated in proteinaceous liquid (eg, plasma) at 35ºC for two to three hours (picture 5). Another phenotypic approach employs rapid colorimetric detection of the enzymes L-proline aminopeptidase and beta-galactosaminidase (C. albicans Screen). In addition, a chromogenic agar culture medium (CHROMagar) allows presumptive phenotypic identification of C. albicans, C. tropicalis, and C. krusei (picture 6), and a modified formula can distinguish C. dubliniensis as well [68]. C. auris colonies reportedly are pink to beige on the chromogenic culture medium and grow well at 42°C [69-71]. Traditional methods can further characterize yeast isolates using carbohydrate assimilation tests, which require two to three days for completion. These nutritional assimilation tests use either manual kits or automated methods. However, not all of these tests reliably identify C. auris isolates and careful testing using updated database software or instrumentation would be needed [70,71].
While many clinical laboratories continue to use traditional phenotypic methods for yeast identification, newer tools are gaining acceptance. These include matrix-assisted laser desorption/ionization time of flight mass spectrometry, which offers the ability to accurately identify yeast isolates, including C. auris, in minutes without the need for mycologic expertise [72-75]. In addition, the T2Candida system is capable of detecting Candida species in blood in as little as four hours. Nucleic acid sequence analysis hold promise for identification of fungal isolates and is a highly effective approach in the research laboratory setting, but as yet, there is no regulatory approval for its wider application. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults", section on 'Blood cultures'.)
Antigenic structure — The multilayered cell wall of C. albicans consists of glucans, mannans, mannoproteins, proteins, and chitin [76-79]. With the exception of glucans and chitin, which have little, if any, antigenicity, these products are capable of eliciting an immune response [80]. Glucan and chitin appear to lend mechanical strength and stability to the cell wall [45]. Strains deficient in one or more of these components are less virulent [77,78,81,82].
VIRULENCE FACTORS — Candida species have little inherent virulence as illustrated by their ability to exist in a commensal relationship with humans and other animals. Despite this fact, the prevalence of Candida infections has increased in recent decades, and the relative numbers of non-albicans Candida infections are increasing [83]. C. albicans, however, still causes the majority of infections. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis", section on 'Prevalence of Candida species'.)
Molecular genetic advances, such as creation of gene knockout mutants, genome sequencing, and proteomic studies permit specific analysis of putative virulence factors [21,84]. It is likely that there are numerous virulence factors, which may play different roles at various sites and stages of a given infection [1,85,86]. As noted above, one such factor appears to be the ambient pH of the host [41-43]. Other examples include calcineurin (a calcium-regulated signaling enzyme) and Hsp90, which have been shown to be important virulence factors [29,87-89]. Calcineurin mutant strains showed no deficits in known virulence factors but were highly attenuated in a murine model of disseminated candidiasis. In addition, inhibition of calcineurin promotes susceptibility to azole antifungal compounds in vivo and in vitro [90,91]. More recently, the GWT1 gene, which encodes an inositol acyltransferase needed for anchoring of fungal proteins to the fungal cell membrane, has been shown to be a potential gene target that provides the basis for a new class of antifungal compounds [22,92].
There also appear to be multiple adherence mechanisms that allow initial attachment to host tissue (or plastic foreign bodies) and subsequent proliferation. For example:
●A hyphal-specific surface protein, Hwp1, is needed to form stable attachments to epithelial cells and in the formation of biofilms [59,93,94]. Hwp1 deficiency resulted in decreased virulence in a murine model of candidiasis [95].
●Mutations in the genes that regulate the switch from budding yeast to a filamentous form result in avirulent strains [52,65,84,96].
●C. albicans deficient in mannosyl transferase demonstrated decreased adherence and virulence [77,97].
In vitro testing has suggested that the ability of C. albicans to synthesize trehalose provides protection against stress factors (such as thermal stress) [98]. In vivo testing of a trehalose synthase mutant strain showed attenuated virulence in a murine model of infection, supporting the further investigation of trehalose phosphate synthase as a potential antifungal compound target [98].
C. albicans also produces extracellular proteinases, phospholipases, lipases, hydrolytic enzymes, and adhesins in vivo [1,43,64,96,99-104]. Among these possible virulence factors, protease-lacking mutants were less virulent than their wild-type parent [1,30,105]. Reduced virulence also was induced by deletion of the gene encoding for the production of phospholipase [106]. This defect did not appear to affect in vitro adhesion but was associated with diminished cell wall penetration. Phospholipase formation reportedly is higher among C. albicans isolates causing infection [43]. In a mouse model, the phospholipase-competent strain had a significantly greater ability to cross the gastric mucosal barrier and invade the kidneys and liver. Mutant strains that lack adhesion Hwp1 showed decreased virulence in an esophageal murine model of candidiasis [107]. Ability to adapt to rapidly changing hypoxic conditions also may be a virulence factor [108-110].
Comparative analysis of the genome of C. albicans with that of the nonpathogenic yeast Saccharomyces cerevisiae has shown that about 7 percent of genes in C. albicans have no homolog in S. cerevisiae. These genes appear to be of the kind that may be responsible for synthesis of adhesions and hydrolytic enzymes, which are believed to be virulence factors [1].
GENETIC FACTORS — Chronic mucocutaneous candidiasis is associated with the genetic conditions polyglandular autoimmune syndrome type I (the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) syndrome and Job's (hyperimmunoglobulin E) syndrome [111-113]. (See "Autosomal dominant hyperimmunoglobulin E syndrome".)
Certain genetic mutations have also been associated with mucocutaneous Candida infections in familial clusters. These are discussed in detail separately. (See "Chronic mucocutaneous candidiasis".)
IMMUNE RESPONSE — Cell-wall constituents in Candida species can evoke both humoral and cellular host immune responses during the course of infection [114,115]. In addition, extracellular proteinases of C. albicans trigger immune responses locally and systemically [1,116]. The cell-mediated immune response is clearly important in host defense against Candida, as reflected by the higher prevalence of infections among individuals whose cellular immune systems are impaired, but the exact mechanisms of induction of this response have not been elucidated. Interleukin (IL-)12 appears to play an important role in the development of a Th1 response to C. albicans in the mouse; IL-12-deficient mice had increased susceptibility to infection introduced via the gastrointestinal tract and also to reinfection [117,118]. The role of interferon (IFN-)gamma seems to be more complex [112,119-121]:
●IFN-gamma knockout mice were more susceptible to Candida infection.
●Experimental infection or IL-12 administration induced a Th1 response in mice associated with IFN-gamma production.
●IL-12 administration to systemically infected mice resulted in uniformly lethal disease, whereas coadministration of IFN-gamma was protective in 70 percent of animals.
In contrast, IL-10 knockout mice displayed resistance to systemic but not gastrointestinal Candida infection [122].
Neutrophils also contribute to host defense against Candida infection [96,115]. Several studies have shown that granulocyte colony-stimulating factor (G-CSF) increased neutrophil-mediated damage to pseudohyphae of C. albicans, perhaps in association with IFN-gamma [123,124]. One study found decreased salivary flow, diminished levels of secretory immunoglobulin (Ig)A, and reduced activity of salivary polymorphonuclear leukocytes in the patients with oral candidiasis compared with healthy controls [125].
The role of the humoral response in preventing disease progression during Candida infection has been unclear and controversial [126-128]. However, polyclonal and monoclonal antibodies have shown a protective effect in a mouse model of candidiasis [129,130]. Mannan-specific IgG antibodies have been shown to trigger both the classical and alternative complement pathways [131]. These findings suggest that development of a vaccine or short-term protective antibodies may be feasible. In both immunocompetent and immunocompromised mice, a vaccine against C. albicans conferred reduced fungal burden and improved survival [118,132]. Toll-like receptors (TLRs), mainly TLR2 and TLR4, play a key role in recognition of C. albicans and the activation of the host immune response [133]. In addition, the non-toll-like receptor Dectin-1 has been shown to induce host cellular responses following recognition of beta-glucan of the fungal cell wall [134,135].
SUMMARY
●Candidiasis refers to the range of infections caused by species of the fungal genus Candida; these infections can be acute or chronic, localized or systemic. Disseminated candidiasis is life threatening. The great majority of candidiasis is caused by Candida albicans although non-albicans infections are increasing in incidence. C. albicans is a common commensal organism in the oropharyngeal cavity, gastrointestinal tract, and vagina of humans but is capable of causing opportunistic infection following disruption of the normal flora, a breach of the mucocutaneous barrier, or a defect in host cellular immunity. (See 'Introduction' above.)
●At least 30 Candida species have caused infection in humans. The most common of these are C. albicans, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis. C. auris was first identified as a cause of infections in 2011, is often multidrug resistant, is associated with outbreaks in health care facilities, and is regarded as a global health problem. (See 'Mycology' above.)
●Unlike the so-called systemic dimorphic fungi (eg, Histoplasma capsulatum), the morphology of a given Candida species is fundamentally the same whether observed in vitro or in vivo. C. glabrata grows as a small, elliptical, unicellular budding yeast at all times (picture 1). In marked contrast, C. albicans, C. krusei, C. parapsilosis, and C. tropicalis form elliptical budding cells that typically are larger than those of C. glabrata; they can also form elaborate and well-developed multicellular filaments (picture 2), particularly when in contact with a solid substrate, such as human tissue or agar culture media. (See 'Growth, morphology, and pleomorphism' above.)
●The presence of budding yeast and filaments in infected tissue is usually indicative of candidiasis. (See 'Growth, morphology, and pleomorphism' above.)
●Cultures can be expected to grow overnight in most cases. Rapid presumptive identification of C. albicans can be made by observing the formation of germ tubes (the initiation of true hyphal growth) when incubated in proteinaceous liquid (eg, plasma) at 35ºC for two to three hours (picture 5) or by rapid colorimetric detection of the enzymes L-proline aminopeptidase and beta-galactosaminidase. Traditionally, definitive identification of yeast species is based on a combination of morphologic features and physiologic testing, but that approach is being eclipsed by alternative methods such as matrix-assisted laser desorption/ionization time of flight mass spectrometry. (See 'Detection in the microbiology laboratory' above.)
●Candida species have little inherent virulence as illustrated by their ability to exist in a commensal relationship with humans and other animals. Nevertheless, several virulence factors have been identified, including the ambient pH of the host, calcineurin, and various adherence mechanisms. Progress in the identification of virulence factors and important genes holds promise for the development of new classes of antifungal compounds. (See 'Virulence factors' above.)
●Chronic mucocutaneous candidiasis is associated with the genetic conditions polyglandular autoimmune syndrome type I (the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) syndrome and Job's (hyperimmunoglobulin E) syndrome. Other genetic mutations have also been associated with mucocutaneous Candida infections in familial clusters. (See 'Genetic factors' above.)
●Cell-wall constituents in Candida species can evoke both humoral and cellular host immune responses during the course of infection. In addition, extracellular proteinases of C. albicans trigger immune responses locally and systemically. The cell-mediated immune response is clearly important in the host defense against Candida, as reflected by the higher prevalence of infections among individuals whose cellular immune systems are impaired. (See 'Immune response' above.)
