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To cite this article: François L. Mayer, Duncan Wilson & Bernhard Hube (2013) Candida albicans
pathogenicity mechanisms, Virulence, 4:2, 119-128, DOI: 10.4161/viru.22913
To link to this article: https://doi.org/10.4161/viru.22913
Abbreviations: AMP, antimicrobial peptide; Hsp, heat shock protein; sHsp, small Hsp; RHE, reconstituted human oral
epithelium; RNS, reactive nitrogen species; ROS, reactive oxygen species
The polymorphic fungus Candida albicans is a member of the C. albicans and to a lesser extent other Candida species are pres-
normal human microbiome. In most individuals, C. albicans ent in the oral cavity of up to 75% of the population.6 In healthy
resides as a lifelong, harmless commensal. Under certain individuals this colonization generally remains benign. However,
circumstances, however, C. albicans can cause infections that mildly immunocompromised individuals can frequently suffer
range from superficial infections of the skin to life-threatening from recalcitrant infections of the oral cavity. These oral infec-
systemic infections. Several factors and activities have been tions with Candida species are termed “oral candidiasis” (OC).6
identified which contribute to the pathogenic potential Such infections are predominantly caused by C. albicans and can
of this fungus. Among them are molecules which mediate affect the oropharynx and/or the esophagus of persons with dys-
adhesion to and invasion into host cells, the secretion of
functions of the adaptive immune system. Indeed, HIV is a major
hydrolases, the yeast-to-hypha transition, contact sensing and
thigmotropism, biofilm formation, phenotypic switching and
risk factor for developing OC. Further risk factors for developing
a range of fitness attributes. Our understanding of when and OC include the wearing of dentures and extremes of age.7
how these mechanisms and factors contribute to infection has It is estimated that approximately 75% of all women suffer at
significantly increased during the last years. In addition, novel least once in their lifetime from vulvovaginal candidiasis (VVC),
virulence mechanisms have recently been discovered. In this with 40–50% experiencing at least one additional episode of
review we present an update on our current understanding infection.8,9 A small percentage of women (5–8%) suffer from at
of the pathogenicity mechanisms of this important human least four recurrent VVC per year.10 Predisposing factors for VVC
pathogen. are less well defined than for OC and include diabetes mellitus,
use of antibiotics, oral contraception, pregnancy and hormone
therapy.11 Despite their frequency and associated morbidity,
superficial C. albicans infections are non-lethal. In stark contrast,
Introduction systemic candidiasis is associated with a high crude mortality
rate, even with first line antifungal therapy.3,4,12 Both neutropenia
The total number of eukaryotic species on Earth has recently and damage of the gastrointestinal mucosa are risk factors for the
been estimated at 8.7 million, with fungi making up approxi- development of experimental systemic (disseminated) candidia-
mately 7% (611,000 species) of this number.1 Of all fungi, only sis.13 Further risk factors include central venous catheters, which
around 600 species are human pathogens.2 This relatively small allow direct access of the fungus to the bloodstream, the applica-
group encompasses fungi that cause relatively mild infections of tion of broad-spectrum antibacterials, which enable fungal over-
the skin (e.g., dermatophytes and Malassezia species), fungi that growth, and trauma or gastrointestinal surgery, which disrupts
cause severe cutaneous infections (e.g., Sporotrix schenkii) and mucosal barriers.14
fungi that have the potential to cause life-threatening systemic During both superficial and systemic infection, C. albicans
infections (e.g., Aspergillus fumigatus, Cryptococcus neoformans, relies on a battery of virulence factors and fitness attributes. The
Histoplasma capsulatum, and Candida albicans). Indeed, Candida major factors and fitness traits are discussed below.
spp are the fourth most common cause of hospital-acquired sys-
temic infections in the United States with crude mortality rates of Pathogenicity Mechanisms
up to 50%.3,4 C. albicans can cause two major types of infections
in humans: superficial infections, such as oral or vaginal candi- The ability of C. albicans to infect such diverse host niches is
diasis, and life-threatening systemic infections (for a comprehen- supported by a wide range of virulence factors and fitness attri-
sive description of C. albicans infections see the second edition of butes. A number of attributes, including the morphological tran-
Candida and Candidiasis5). sition between yeast and hyphal forms, the expression of adhesins
and invasins on the cell surface, thigmotropism, the formation
*Correspondence to: Bernhard Hube; Email: Bernhard.Hube@hki-jena.de of biofilms, phenotypic switching and the secretion of hydro-
Submitted: 10/12/12; Revised: 11/15/12; Accepted: 11/15/12 lytic enzymes are considered virulence factors. Additionally,
http://dx.doi.org/10.4161/viru.22913
fitness attributes include rapid adaptation to fluctuations
in environmental pH, metabolic flexibility, powerful nutri- C. albicans, the main quorum sensing molecules include farne-
ent acquisition systems and robust stress response machineries sol, tyrosol and dodecanol.23-25 Due to quorum sensing, high cell
(Fig. 1).15 densities (> 107 cells ml-1) promote yeast growth, while low cell
Polymorphism. C. albicans is a polymorphic fungus that can densities (< 107 cells ml-1) favor hyphal formation.
grow either as ovoid-shaped budding yeast, as elongated ellipsoid The transition between yeast and hyphal growth forms is
cells with constrictions at the septa (pseudohyphae) or as par- termed dimorphism and it has been proposed that both growth
allel-walled true hyphae.16 Further morphologies include white forms are important for pathogenicity.26 The hyphal form has
and opaque cells, formed during switching, and chlamydospores, been shown to be more invasive than the yeast form.16 On the
which are thick-walled spore-like structures.17 While yeast and other hand the smaller yeast form is believed to represent the
true hyphae are regularly observed during infection and have dis- form primarily involved in dissemination.27
tinct functions (as discussed below), the role of pseudohyphae Mutants that are unable to form hyphae under in vitro con-
and switching in vivo is rather unclear and chlamydospores have ditions are generally attenuated in virulence.28 However, hypha
not been observed in patient samples.18,19 formation is linked to the expression of a subset of genes encod-
A range of environmental cues affect C. albicans morphology. ing virulence factors that are not involved in hyphal formation
For example, at low pH (< 6) C. albicans cells predominantly per se. Such hypha-associated proteins include the hyphal wall
grow in the yeast form, while at a high pH (> 7) hyphal growth protein Hwp1, the agglutinin-like sequence protein Als3, the
is induced.20 Indeed, a number of conditions, including starva- secreted aspartic proteases Sap4, Sap5 and Sap6 and the hypha-
tion, the presence of serum or N-acetylglucosamine, physiologi- associated proteins Ece1 and Hyr1. Deletion of HGC1, which
cal temperature and CO2 promote the formation of hyphae.21 encodes a hypha-specific G1 cyclin-related protein, results in cells
Morphogenesis has also been shown to be regulated by quo- that grow normally in the yeast form but fail to produce hyphae.
rum sensing, a mechanism of microbial communication.22 In Nevertheless, the hgc1Δ/Δ mutant cells still express at least four