Microbe Profile : Candida albicans : a shape-changing , opportunistic pathogenic fungus of humans

Candida albicans is normally a harmless commensal of human beings, but it can cause superficial infections of the mucosa (oral/vaginal thrush) in healthy individuals and (rarely) infections of the skin or nails. It can also become invasive, causing life-threatening systemic and bloodstream infections in immunocompromised hosts, where the mortality rate can be as high as 50%. It is the most common cause of serious fungal infection and is a common cause of nosocomial infections in hospitals. Some strains have been recognized that are resistant to azoles or echinocandins, which are the first-line antifungals for treatment of C. albicans infections. Received 24 February 2017; Accepted 5 June 2017 Author affiliation: The Aberdeen Fungal Group, MRC Centre for Medical Mycology, School of Medicine, Medical Science and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB252ZD, UK. *Correspondence: Neil A. R. Gow, n.gow@abdn.ac.uk

TAXONOMY First description in 1839 by Langenbeck. Candida -Latin candidus, meaning 'gleaming white'; albicans -Latin albicare, meaning 'to whiten', suggestive of the white exudate on the infected mucosal surfaces.
Superkingdom Eukaryote, kingdom Fungi, subkingdom Dikarya, phylum Ascomycota, subphylum Saccharomycotina, class Saccharomycetes, subclass Saccharomycetidae, order Saccharomycetales, family Metschnikowiaceae, genus Candida, species albicans. PROPERTIES C. albicans is highly polymorphic (see the graphical abstract), switching in vivo to alternative vegetative growth forms in response to changing environmental conditions such as nutrient availability, temperature, pH, CO 2 and the presence of serum [1]. This phenotypic flexibility is an important virulence factor that aids in its invasion of epithelia, dissemination throughout the host and survival in different host niches, and also helps to modulate the host immune response and counteract immune surveillance. It is highly metabolically flexible and can utilize different nutrient sources simultaneously through post-transcriptional rewiring and constitutive expression of alternative metabolic pathways [2].

GENOME AND EVOLUTION
C. albicans was one of the first eukaryotic pathogens to have its genome sequenced [3]. Clinical isolates have a 16 Mb genome, with 33.3 % GC content, 132 non-coding RNAs, a number of transposons, 8 diploid chromosomes and 6735 (haploid) ORFs. The C. albicans genome is highly plastic and high levels of heterozygosity, intra-chromosome recombination and aneuploidy can be observed between genomes of different strains. The loss of heterozygosity, chromosomal rearrangements and whole chromosome or segmental aneuploidies lead to stress adaptation and can also affect drug sensitivity by influencing the copy number of key drugresistance alleles [4]. Many key virulence-associated functions are performed by multi-gene families, some of which have evolved by sub-telomeric gene duplication and expansion.
Even though haploid forms of C. albicans have been identified [5], and fusion of opposite mating types has been observed [6], no full meiotic sexual cycle has been discovered. The populations observed in a single host are mostly clonal in nature. Under stressful environmental conditions it has been shown to undergo a parasexual cycle where two diploids of opposite mating types fuse to form tetraploid zygotes that undergo concerted chromosome loss to give rise to near diploids. PHYLOGENY C. albicans belongs to a limited CTG clade of asexual Candida species in the Saccharomycetales order, which decode the codon CTG as Ser instead of Leu [7], resulting in practical difficulties in expressing heterologous gene sequences. Whole-genome sequence analysis and comparisons with other Candida species of the CTG clade have shown the expansion of many gene families, conferring pathogenicity, by gene duplication in C. albicans which makes it the most pathogenic of the Candida species. The closest relative is Candida dubliniensis, although there is no correlation between phylogeny and relative virulence. Some other pathogenic Candida species are haploid.

KEY FEATURES AND DISCOVERIES
C. albicans lives asymptomatically as a commensal of warm-blooded animals. No environmental reservoirs are known. It is transmitted from mothers to neonates and by nosocomial infection. Between 30-70 % healthy individuals carry at least one Candida species commensally. However, it causes life-threatening and fatal bloodstream and invasive systemic infections in immunocompromised individuals and upon breaching of protective mucosal barriers during trauma and surgical interventions. This is also promoted when the suppressive host microbiota is inhibited [8].
During the course of infection, C. albicans can manipulate the host immune response by altering its cell-wall components, changing cell shape and secreting various virulence factors. Its cell wall is a bilaminate structure composed of outer fibrillar mannoproteins and an inner core of b-glucans and chitin that all contribute to the immune response. Changes in the structure and composition of the wall occur in different host microenvironments and in response to the action of antifungal drugs. This can prevent or interfere with phagocytosis and inhibit or modulate the protective Th1, Th17 and inflammasome immune responses, and activate the anti-inflammatory Th2 response, leading to tolerance [9]. Phagocytosed yeasts can form hyphae and induce pyroptosis (a form of apoptosis caused by NLRP3 inflammasome activation). Even if phagocytosed, it has the ability to induce its own non-lytic expulsion and prevent acidification and maturation of the phagolysosomes of macrophages, and to express detoxifying enzymes to counteract ROS/RNS-induced damage in the phagosome.
It expresses invasins that induce its uptake by epithelial cells, and adhesins that confer the ability to adhere to several biotic and abiotic surfaces (such as medical implants and catheters), and forms drug-resistant biofilms. It also secretes several hydrolytic enzymes (e.g. proteases and lipases), zincscavenging proteins and a pore-forming toxin called candidalysin [10], which aids tissue penetration and results in damage of host epithelia and activation of immune responses.
C. albicans can inhibit host complement activation, inactivate antimicrobial peptides and inhibit other immune cell functions, thus weakening host defences. Antifungal drugs targeting cell-wall b-1,3 glucan (echinocandins) or the ergosterol biosynthesis pathway (azoles) are used as first-line options to treat infection, but C. albicans can develop resistance via the upregulation of azole efflux pumps, the acquisition of mutations affecting the structure or expression of the azole target CYP51 (cytochrome P450 lanosterol 14ademethylase), or the induction of compensatory changes in chitin in the cell wall in response to echinocandins.

OPEN QUESTIONS
. An in-depth understanding of the determinants of pathogenicity, adaptability and fitness of C. albicans needs to be developed. . The roles of many of the cell-wall proteins and other surface components in the immune response and in disease are not fully understood. . Studies of the variability in individual host responses and the influence of human genetic polymorphisms in determining the outcome of Candida infections is generating opportunities to design personalized therapeutic options. . Diagnostics that distinguish commensal carriage and invasive disease are needed. High mortality is often associated with failure to make an early and accurate diagnosis. . Research towards developing an anti-Candida vaccine is urgently required.

Funding information
The authors received funding support from Wellcome Trust (086827, 075470, 101873 and 200208) and the MRC Centre for Medical Mycology (N006364/1).