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Candida albicans - Biology, molecular characterization, pathogenicity, and


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DOI: 10.1016/j.micpath.2018.02.028

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Microbial Pathogenesis 117 (2018) 128–138

Contents lists available at ScienceDirect

Microbial Pathogenesis
journal homepage: www.elsevier.com/locate/micpath

Candida albicans - Biology, molecular characterization, pathogenicity, and T


advances in diagnosis and control – An update
Maryam Dadara,∗, Ruchi Tiwarib, Kumaragurubaran Karthikc, Sandip Chakrabortyd,
Youcef Shahalia, Kuldeep Dhamae
a
Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
b
Department of Veterinary Microbiology and Immunology, College of Veterinary Sciences, UP Pandit Deen Dayal Upadhayay Pashu Chikitsa Vigyan Vishwavidyalay Evum
Go-Anusandhan Sansthan, Mathura, Uttar Pradesh, India
c
Central University Laboratory, Tamil Nadu Veterinary and Animal Sciences University, Chennai, Tamil Nadu, India
d
Department of Veterinary Microbiology, College of Veterinary Sciences and Animal Husbandry, R.K. Nagar, West Tripura, India
e
Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India

A R T I C L E I N F O A B S T R A C T

Keywords: Candida albicans is an emerging multidrug-resistant fungal pathogen representing an important source of in-
Candida albicans vasive disease in humans and generating high healthcare costs worldwide. This fungus is frequently found in
Fungal pathogen different anatomical sites of healthy persons and could induce systemic and superficial infections under optimal
Epidemiology environmental conditions. Invasive candidiasis (IC) is an important nosocomial infection with high morbidity
Molecular typing
and mortality rates in hospitalized children. It represents a major source of prolonged infections in intensive care
Pathogenicity
unit (ICU), particularly in immunosuppressed or elderly patients. Clinical diagnosis of candidiasis could be
Virulence factors
Diagnosis difficult because of the lack of specific symptoms and clinical signs. Although C. albicans is the most frequently
Prevention isolated Candida species in IC, non-albicans Candida (NAC) species are also commonly detected. Multilocus
Control enzyme electrophoresis (MLEE), fragment length polymorphism (RFLP), electrophoretic karyotyping (EK), and
random amplified polymorphic DNA (RAPD), multilocus sequence typing (MLST) are known as an efficient
technique used for molecular typing of Candida species. The efficacy of antifungal treatment against candidiasis
has been evaluated and discussed in the context of large epidemiological studies. The present review highlights
the etiology, epidemiology, molecular typing, commensalism and virulence factors, along with the appropriate
prevention and control strategies regarding this widespread pathogen.

1. Introduction reduction of pH may result in candidiasis [143]. It has been demon-


strated that C. albicans systemic infections lead to a mortality rate of
Candida albicans and other emerging NAC species, including ∼40% [66]. C. albicans is the major species responsible forinvasive
Candida glabrata, Candida krusei, Candida tropicalis, and Candida para- candidiasis (46.3%), followed by C. glabrata (24.4%) and C. parapsilosis
psilosis represent an important source of systemic infections worldwide. (8.1%) [5]. As a commensal pathogen, Candida can adapt to hosts'
These organisms are the most common cause of superficial vaginal or environmental changes very quickly, even when nutrients bioavail-
mucosal oral infections and may also, under propitious conditions, ability is restricted [116]. The outcomes of C. albicans infections within
enter the bloodstream leading to deep-tissue infections the damage response framework can fit into six classifications taking
[40,186,198,198]. C. albicans is a member of the human microflora as a into account the associated host immune response, the anatomical site
diploid polymorphic yeast of mucosal surfaces and is commonly found of infection, the Candida virulence; the morphology of hyphae and
in the human gastrointestinal (GI), respiratory, and genitourinary hyphae-specific gene expression as critical factors for virulence
tracts. It is generally a harmless commensal fungus that can turn into an [72,183]. Remarkably, the morbidity associated with C. albicans in-
opportunistic organism in immunocompromised or immunologically fections mainly depends on the associated host immune responses and
deficient individuals. With a variety of host cells, including Th17 cell, affected tissues/organs. Virulence, epidemiology, and antifungal sus-
this microorganism can interact during the disease manifestations [77]. ceptibility of all Candida species differ, but the term candidiasis is
An abnormal growth in C. albicans due to environmental imbalance like commonly referred to as an invasive candidiasis caused by Candida


Corresponding author.
E-mail address: maryamdadar@rvsri.ac.ir (M. Dadar).

https://doi.org/10.1016/j.micpath.2018.02.028
Received 15 December 2017; Received in revised form 4 February 2018; Accepted 13 February 2018
Available online 16 February 2018
0882-4010/ © 2018 Elsevier Ltd. All rights reserved.
M. Dadar et al. Microbial Pathogenesis 117 (2018) 128–138

ubiquitous yeasts. Since Candida species may superficially colonize The highest prevalence was reported in the USA [38] where the noso-
healthy hosts without causing any notable damage, active immune re- comial candidemia represents an important threat [14]. The most im-
sponses against antigens of Candida can be also detected in im- portant risk factors for incidence of Candida BSI are parenteral nutri-
munocompetent individuals [27,170]. tion, broad-spectrum antibiotics, immuno-suppression induced by
The most important risk factors for C. albicans infections are anti- radiotherapy or chemotherapy, interruption of mucosal barriers be-
biotic therapy followed by central venous access, surgical procedures, cause of surgery, ICU admission, and indwelling medical devices (e.g.,
neutropenia, parenteral nutrition, urinary catheter, as well as some central venous catheters) [45,93]. Accurate identification of specific
disease such as hematologic malignancy, solid cancer, prematurity, Candida species could control the risk for nosocomial infections and
cardiac disease, trauma, neurologic disease, gastrointestinal disease, exogenous transmission in certain patient populations [180].
organ transplant, pulmonary disease, vascular disease, HIV, genetic Incidence-related risk factors for Candida colonization vary between
disease/congenital malformation, renal disease, diabetes mellitus, liver C. albicans and NAC. Moreover, oral hygiene, and systemic and living
disease and pancreatic disease [25]. In severely immunocompromised conditions including dietary uptake of nutrients play critical roles in the
individuals, C. albicans induces systemic infection [81] and may turn prevalence of both C. albicans and NAC infections among populations of
from local opportunistic or commensal infections of the mouth, throat, different countries [13,162]. More than 60% of the Candida isolates
and reproductive tract to a systemic invasive candidiasis affecting the were identified as C. albicans; while NAC was identified in 8.6% of
circulatory system, bones, and brain [80]. In atopic and allergic in- symptomatic patients and 14.3% of asymptomatic patients [19]. In
dividuals, the chronic exposure to C. albicans act as an aggravating young individuals the highest mortality results from infections caused
factor in atopic dermatitis (AD) and lead to the production of specific by general purpose genotype (GPG) of C. albicans.
immunoglobulin E (IgE) against C. albicans antigens [51,164]. More Another study of patients with invasive candidiasis, documented
recently, C. albicans emerges as a novel pathogenic candidate in bipolar from 2011 to 2013 in southwest of China, reported that although C.
disorder and schizophrenia [176]. This review highlights the most re- albicans was the most frequently isolated Candida species (48.6% of all
cent evidences that C. albicans competes out opportunistic pathogens in invasive candidiasis patients), NAC species were also commonly iso-
invasive candidiasis. We also review important features of candidiasis lated [149]. In addition, swab samples of vaginal secretion collected
regarding its etiology, epidemiology, molecular characterization, and from 200 Iranian patients with clinical VVC revealed that C. albicans
typing of pathogenic species to improve the diagnostic, prevention and species accounted for 67% of single and mixed infections [151]. Re-
control of this widespread disease. portedly, the prevalence of denture stomatitis due to C. albicans was
relatively significant in a cohort of 2271 infected patient in Iran
2. Etiology and epidemiology of candidiasis reaching 28.9% [119]. Furthermore, many other studies have high-
lighted the importance of C. albicans as the primary pathogen causing
Candida infection is the main cause of nosocomial bloodstream in- stabilized and exacerbated denture stomatitis in 93% of affected pa-
fections (BSIs) in tertiary care hospitals worldwide. The incidence of tients [23]. An epidemiological study of patients admitted to 26 Spanish
candidemia caused by strains that are resistant to fluconazole is high. hospitals reported that C. albicans was the most common species iso-
Candida spp. are also responsible for chronic infections in the ICU in- lated from patients with invasive candidiasis, even though cases with
patients and in hospitalized children, leading to important healthcare NAC infections were apparently increasing [129] (see Table 1).
costs [55,64,157,179]. Candida species were reportedas the fourth most
common cause of blood-borne microbial infections [85]. 3. Molecular typing of C. albicans
Fifteen Candida species can be pathogenic for humans, but more
than 90% of reported invasive candidiasis are associated with the five Molecular typing is an efficient technique used to examine the po-
most common species i.e. C. albicans, C. glabrata, C. parapsilosis, C. pulation structure and epidemiological characteristics of fungal pa-
krusei, and C. tropicalis. Although the recent rise in the number of these thogens, yielding valuable information on the dynamics of C. albicans
infections [138,186] ismainly associated toC. albicans, NAC-related infections in human populations [161]. The assessment of genetic re-
diseases are also increasingly reported in different parts of the world latedness of the organism has become much easier with the spread of
[110]. For example, the vulvovaginal candidiasis (VVC) that affects molecular typing methods. This approach allowed the determination of
millions of women every year is mainly caused by C. albicans, but NAC several clusters for different C. albicans genotypes [16,103].
species, especially C. glabrata, have been reported as a cause of this Multilocus enzyme electrophoresis (MLEE) is based on the differ-
infection [60,200]. The virulence, epidemiology, and susceptibility to ential electrophoretic mobility of approximately ten enzymes making
antifungal drugs differ among different pathogenic species responsible possible to achieve reproducible fungal phenotyping outcomes [28].
for invasive candidiasis [68,137]. However, this technique has been widely replaced with restriction
Regarding the intra-abdominal candidiasis (IAC), the most common fragment length polymorphism (RFLP) analyses along with electro-
type of deep-tissue candidiasis, the antifungal treatment trials and di- phoretic karyotyping (EK) and random amplified polymorphic DNA
agnostics are not well understood compared to those for candidemia (RAPD) analyses [178]. All these techniques are somewhat limited
[9]. Due to the frequently combined infections of Candida with bacteria because of low inter-laboratory reproducibility of their respective re-
and the lack of beneficial antifungal treatments for IAC, the clinical sults. To overcome these limitations, whole-genome DNA sequencing
significance of the presence of Candida spp. in samples cultures from has l substituted the molecular-typing techniques applied to C. albicans
intra-abdominal tissues remains controversial [118,158,189]. strains, improving the typing methods through the powerful compar-
The use of molecular tools has generated a large amount of in- ison of DNA sequences [103]. Besides, multilocus sequence typing
formation about the biology of Candida. This has enabled the diagnosis (MLST) of C. albicans isolates, based on DNA sequencing of PCR-am-
of emerging Candida species using efficient molecular approaches such plified 300–400-bp regions of seven housekeeping genes, and re-
as internal transcribed spacer (ITS) sequencing. Polymorphism analysis presents a highly reproducible and sensitive technique providing a
of rDNA regions by ITS appeared to be advantageous as a distinguishing discriminatory power compatible with that of Ca3-based fingerprinting.
genetic marker in studying molecular phylogenetics and epidemiology, MLST also represents a valuable method for understanding the popu-
species identification, and for documenting the natural history of can- lation structure and epidemiology of systemic Candida infections
didiasis. This method allowed the identification of emerging Candida [39,132,202]. Comparative studies using MLST are available online on
species as a source of hematogenous infections [10,26,29,130]. The the curated MLST database of C. albicans (http://calbicans.mlst.net/).
global prevalence of candidemia highly varies in different parts of the Reportedly, MLST clade 1 is the most common MLST cluster among
world, ranging from 1.1 to 14.4 out of every 105 cases [6,57,131,134]. related strains of C. albicans. Clade 2 is mainly prevalent in the United

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M. Dadar et al. Microbial Pathogenesis 117 (2018) 128–138

Table 1
Prevalence of different Candida species associated with specific clinical outcomes (%).

Clinical description Number of Candida non-Candida albicans (NCA) species (%) years References
patients albicans

Acquired Immunodeficiency Syndrome 24 100 - 1990 [199]


Immunocompromised patients with 116 59 C. glabrata (2) 1993–1999 [15]
cancer
Patients with solid tumors 90 70 C. glabrata (30) 1999 [191]
Exogenous nosocomial acquisition 98 92 – 1993 [188]
Candidemia 345 51 Candida parapsilosis (23), Candida tropicalis (10), Candida glabrata (8), 2005 [3]
Candida krusei (4), and other species (3)
Vulvovaginal candidiasis 200 67 Candida glabrata (18.3), Candida tropicalis (6.8), Candida krusei (5.8), 2011 [151]
Candida parapsilosis (1.6), and Candida guilliermondii (0.5)
Invasive candidiasis (IC) 2496 – C. glabrata (46.4), C. parapsilosis (24.7), C. tropicalis (13.9), C. krusei (5.5), 2004–2008 [145]
C. lusitaniae (1.6), C. dubliniensis (1.5) and C. guilliermondii (0.4)
Invasive candidiasis (from 26 705 43 C. glabrata (31.6), C. parapsilosis (31.6), C. tropicalis (8.3), C. krusei (5), C. 2011–2012 [129]
hospitals) famata (2.5) and other minority species (4.2)
Candidemia 275 42.9 C. glabrata (28) 2007–2015 [78]
Denture stomatitis 2271 82 - 2016 [119]
ICU patients with candidemia 64 34.3 C. parapsilosis (24.1), C.tropicalis (15.3) C.glabrata (10.2) 2007–2010 [46]
Invasive candidiasis 639 46.3 C. glabrata (24.4) C.parapsilosis (8.1) 2016 [5]
Neonatal candidemia (aged < 28 days) 5075 43.5 C.glabrata (33.3), C.tropicalis (20.3), C.parapsilosis (1.4), C.kefyr (1.4) 2017 [56]
ICU patients 340 58.7 C.tropicalis (24), C.parapsilosis (17.3) 2018 [43]
Candidemia 79 44 C. glabrata (19), C. tropicalis (19), C. parapsilosis (14), C. orthopsilosis (4) 2014–2015 [25]

Kingdom, clade 4 comprises isolates from the Middle East and Africa, mitogen-activated protein kinase pathway through Cph1, the cAMP-
clade 11 includes isolates from continental Europe, while isolates from dependent protein kinase pathway via Efg1, and Tup1-mediated re-
the Pacific region belong to a cluster regrouping the clades 14 and 17 pression through Rfg1 and Nrg1. Moreover, surface proteins are also
[131]. More recently, recovered MLST isolates from bloodstream in- critical in the interactions between the fungal cells and various con-
fections in South Korea have emerged as a novel Asian clade [177]. stitutive or inducible host defense mechanisms that are activated during
Molecular fingerprinting of C. albicans did not support intra-hospital candidiasis [174]. For example, the putative NADH-ubiquinone-related
transmission of C. albicans isolated from candidemia patients in Kuwait proteins, Ali1, Mci4, Orf19.287, and Orf19.7590, are implicated in
[7]. A retrospective single-center study of Candida species distribution oxidative and osmotic resistance, yeast-to-hypha transition, and the
in a hospital located in Mexico City showed that microsatellites re- capability to infect and damage oral epithelial cells [59]. Moreover,
present a reliable method for molecular typing and genetic analysis of filamentation reportedly protects C. albicans from amphotericin B-in-
Candida isolates. This study reported a clonal population including 62 duced programmed cell death through a mechanism involving the yeast
identified genotypes among the tested isolates [65]. metacaspase, MCA1 [87]. An overview regarding the dual life cycle of
C. albicans and its transition from commensal to virulent form is illu-
strated in Fig. 2.
4. C. albicans commensalism and virulence factors C. albicans and its cell-wall β-glucans are able to stimulate monocyte
reprogramming as one of the main immunological responses in infected
Yeast and hyphal cells are the two most important morphological hosts [150]. Cheng and his colleagues showed that β-glucan produced
forms of C. albicans that condition its virulence [201]. Transition from by C. albicans increased the expression of some inflammatory cytokines
yeast to hyphae determines C. albicans commensal and pathogenic upon consequent LPS challenges of infected hosts [33,34]. Moreover,
states and may lead to tissue infection, macrophage evasion, host-cell active pathogen-associated molecular pattern molecules masking by a
adhesion, and development of clinically relevant biofilm communities Candida species could compromise detection of the fungus by the im-
[190]. Therefore, post-transcriptional mechanisms underlying this mune system [8]. Interestingly, interactions between host defense re-
morphological transition control C. albicans virulence processes by in- sponses and C. albicans revealed that members of the zinc-cluster-factor
fluencing mRNA stability, alternative transcript localization and family changes C. albicans virulence [71]. Infections to the C. albicans
translation [75]. Moreover, the C. albicans fibrin Sac6 modulates mor- strain PCA-2 was accompanied by high number of peripheral blood
phogenesis and oxidative stress responses at the transcriptional level polymorphonuclear cells and by activation of spleen cells leading to
[203]. Besides, metabolic adaptation is involved in the vulnerability of highly potent candidacidal effects in vitro [11]. In case of genitourinary
C. albicans to antifungal medicines and also influenced key virulence tract infections, the relevant virulence factors were reported as pro-
agents, stress resistance and fungal susceptibility to innate immune teinase and phospholipase [187]. Possible species-related differences in
responses [22]. C. albicans is maintained in its commensal form by a colonization dynamics or pathogenicity of Candida has been proposed
tripartite interaction that involves the organism, resident microbiota [78]. Moreover, different morphologies of C. albicans undergo certain
and immunity of the host. The gastro-intestinally induced transition interactions with host cells during an infection [37]. It was suggested
(GUT) highlights how C. albicans can use distinct genetic pathways for that epithelial mechanisms drive mucosal tissues in order to dissociate
the transition between commensal and invasive pathogenic states the pathogenic and commensal states of C. albicans [155,182]. For ex-
[128,136] before infecting epithelial cells through two specific me- ample, C. albicans cells treated with a medicinal plant extract of Rho-
chanisms, i.e. active penetration and endocytosis [52,194]. domyrtus tomentosa, showed adeclined adhesion to surfaces, thereby
Candida spp. virulence factors include: morphological transition inhibiting virulence factors of C. albicans [70].
between yeast and hyphal forms; cell surface expression of adhesins and In addition, phosphate metabolism has been shown to slightly affect
invasions; biofilm formation; thigmotropism; phenotypic switching and virulence of the different clades of C. albicans [99] while the blocking of
hydrolytic enzyme secretion. Many phase-specific genes and hypha- two-component signaling led to elevate the virulence of C. albicans as
specific genes express proteins directly or indirectly drive pathogenesis an adaptive mechanism interacting with stress-activated protein kinase
and virulence of C. albicans [95,107]. These major pathways regulate [44]. Another study revealed that secreted C. albicans protein Pra1,
expression of hypha-specific and/or phase-specific genes, including the

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M. Dadar et al. Microbial Pathogenesis 117 (2018) 128–138

which is known as a fungal protease, could disrupt host innate im- uses glucose as the preferred carbon source through three anticipated
munity through blocking the complement C3 and C3 activation frag- approaches leading to the transport and metabolism of glucose [159].
ments [98]. The pathways of sugar receptor–repressor include the glucose repres-
C. albicans also triggers NLRP3-mediated pyroptosis in macro- sion pathway and the adenylate cyclase pathway. Moreover, C. albicans
phages enabling them to escape macrophage defenses. Moreover, C. uses multiple other carbon sources in the host. During infection of tis-
albicans-infected bone-marrow-derived macrophages and murine J774 sues and organs, a signature shift in gene expression is seen towards
macrophages undergo pyroptotic cell death that could be suppressed by using alternative carbon sources through upregulation of other path-
glycine and pharmacological inhibitors of caspase-1 [197]. ways, including gluconeogenesis, glyoxylate cycle, and β-oxidation of
Alteration of the environmental pH is another mechanism by which fatty acids. Also, mutations in genes responsible for paving pathways
pathogenic fungi defeat the host defenses [192]. Reportedly, C. albicans that use alternative carbon sources attenuate virulence and represent
has evolved multiple pathways for regulating the pH of host environ- pleiotropic phenotypes in C. albicans [153]. For example, coconut oil
ments to maintain its virulence [42]. Moreover, C. albicans acidifies the could be used as the first dietary intervention to reduce colonization of
environment in a carbohydrate-dependent manner, resulting in aspartyl C. albicans in GI [66]. As amino acids are the main source of nitrogen
proteases production, which is an important virulence factor [126]. C. for C. albicans growth and Gap4, a member of amino acid permease
albicans strains can use amino acids as a carbon source allowing them to family, is necessary for S-Adenosylmethionine (SAM)-induced mor-
neutralize the acidic environment of the macrophage phagosomes by phogenesis [83].
signaling through the transcription factor Stp2 [115]. Thus, it has been Studies have shown that in C. albicans there is a close association
shown that the SPS system (abbreviation for the three components of between hypoxia and the initiation of hypha formation, especially when
SSY1, an amino acid transporter homolog, PTR3, peripherally mem- using embedded agar [62]. Different gap mutants that cause changes/
brane associated protein, and SSY5, a chymotrypsin-like serine en- defects in hypha formation and colony morphology of C. albicans were
doprotease) is critical for resistance of C. albicans to macrophages. tested on several solid media to induce morphological changes (Spider,
Moreover, the SPS system is stimulated under carbon-source starvation SLAD, LEE medium, and medium containing N-acetylglucosamine)
conditions resembling the host environment modulating by this way the [74,90,96,101,154] and a control group as SLD and YNB media con-
necessary Stp2 for the catabolism of amino acids and the fungal inter- taining NH4 was designed. It was found that all investigated strains had
actions with innate immune cells [115,116]. Recent studies reported smooth colonies on the control media. Strains such as gap1Δ/gap1Δ
that metabolism intrudes upon the chromatin for transcriptional control mutant also showed comparable hyphal morphogenesis under hypha-
of macrophage activation [86]. The mechanisms of escaping macro- inducing conditions. For example, a defect in morphogenesis was ob-
phages and immune evasion by C. albicans are depicted in Fig. 1. served in the Spider medium [12]. Slightly defective hypha formation
was observed only in the GAP3-deletion strain in Spider medium; hy-
5. Genetic instability of C. albicans phae started to generate two days later when comparedall other dele-
tion or wild-type strains. The same phenotype was reported for three
C. albicans has significant phenotypic and genetic diversity [41]. It independent gap3Δ/gap3Δ mutants. In addition, morphogenesis defects
contains a diploid genome with 14.4 megabases that is arranged as 8 were observed in the gap4Δ/gap4Δ strain on SLD and SAM media. Co-
chromosomes [21]. The heterozygosity and heterozygous of genome is lonies of this strain were smooth, and they did not grow hyphae even
thought to be related with C. albicans virulence [24]. In addition, it is after seven days of prolonged incubation [83]. Moreover, N-acet-
now well documented that genomic instability of C. albicans play a ylglucosamine-inducible CaGAP1 reportedly expressed a common
major role in its pathogenesis [163]. Also, strain-specific differences of amino acid permease regulating morphogenesis and responses to ex-
fungal species may contribute on the interaction of C. albicans and host ternal nitrogen-source in C. albicans [12]. In addition, changing the
[21]. The genetic instability of C. albicans can modulate the candida carbon source of C. albicans alters virulence in models of systemic
behavior at the host interface, the growth rate, the morphology, re- candidiasis and vaginitis, suggesting that alternative carbon sources
sistance to stressors including antimicrobial peptides or antifungals and within host niches are important during different kinds of infections
the fungus pathogenicity during mucosal and systemic infection with C. albicans [49]. Besides, changes in nutrient bioavailability induce
[21,168]. For instance, C. albicans can change its genetic pathways morphological flexibility and are associated with the deregulation of
underlying resistance to iron reduction in the bloodstream to those glutathione levels and isocitrate lyase activity, reflecting the fact that
underlying iron toxicity in the gut during the commensal–pathogenic preservation of intracellular redox equilibrium is important for the
transition [32]. adaptive metabolism of C. albicans [20,193].
There is a non-random distribution of genes over chromosomes of
this microorganism. The C. albicans genome is highly plastic, and 7. Candidiasis in animals
clinical isolates show various karyotypes [35,160]. In response to some
stresses, including heat shock, host–pathogen interactions, and pre- C. albicans is globally distributed in different animals. It is a normal
sence of antifungal drugs, chromosome rearrangements are well toler- opportunistic flora of the GI, respiratory tracts, and the external geni-
ated in C. albicans [17,54,171]. Genomic plasticity in C. albicans can be talia of various animals. All domestic animals, including birds, cattle,
reflected as polymorphisms, cryptic mating, chromosomal inversions, horses, pigs, cats, and dogs are susceptible to Candida infections [47]. C.
copy number variations, recombination, loss of heterozygosity (LOH), albicans causes thrush in domestic poultry, water fowls and wild birds;
subtelomeric hypervariation, and whole or partial chromosome aneu- mainly affecting upper digestive tract of young birds. Affected birds
ploidies [69,172]. Therefore, phenotypic differences and intraspecies revealed pseudomembrane or diphtheritic membranes, and multifocal
genetic diversity have been shown to provoke natural mutations that to confluent mats of cheesy material in the crop with presence of round
change the balance between pathogenicity and commensalism in C. raised ulcers giving a look of ‘Turkish-towel’ in the mucosa. Candida
albicans [168]. Moreover, the intraspecies diversity of C. albicans trig- species induce arthritis in horses [100], and mastitis [53] and abortion
gers qualitatively and temporally distinct host responses that determine [73] in cattle. Candida species have been reported in urinary tract in-
the balance between commensalism and pathogenicity. fections in dogs and cats [148]. Moreover, a case of mycotic en-
dophthalmitis caused by C. albicans has been reported in dogs [94].
6. The relevance of C. albicans and host nutrient levels Moreover, Candida-induced peritonitis with perforating intestinal le-
sions after surgery have been reported in dogs [133], while mucosal
Several important nutritional signals help to regulate morphogen- and cutaneous candidiasis has been demonstrated in im-
esis and pathogenesis during C. albicans infection [76]. The organism munosuppressed [121,195] and diabetic dogs [141]. Using

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M. Dadar et al. Microbial Pathogenesis 117 (2018) 128–138

Fig. 1. Macrophage evasion by Candia albicans. 1) C. albicans triggers NLRP3-mediated pyroptosis in macrophages. Pyroptosis is suppressed by glycine and pharmacological inhibitors
of caspase-1 2) & 3) Alteration of the environmental pH by pathogenic fungi is another mechanism by which the fungus defeats the host defenses. C. albicans uses amino acids as a carbon
source allowing the neutralization of the acidic environment of the macrophage phagosomes by signaling through the transcription factor Stp2. SPS system is critical for resistance of
C. albicans to macrophages. 4) β-glucan produced by C. albicans elevates the host's capability to stimulate expression of some inflammatory cytokines. 5) Active PAMPs masking by
Candida species could compromise detection of the fungus by the immune system.

PCR–restriction-enzyme analysis (REA) C. albicans was identified as the available for sensitive and rapiddiagnosis of invasive candidiasis
etiological agent in a dog suffering from diffuse cutaneous candidiasis [92,117,184]. Some of these diagnostic approaches include detection of
[121]. Accordingly, all domestic animals could be reservoirs or vectors Candida DNA and detection of circulating fungal antigens in serum.
for transmission of C. albicans strains causing human candidiasis and Commercial tests are available for detecting and measuring BDG,
thereby posing a potential risk for immunocompromised patients. Mannan-Ag and Cand-TecTM Candida-antigen (CA); while promising
Although, many reports of candidiasis in animals as well as humans techniques using nucleic acid amplification have yet to be standardized
have been documented [108,127,148,156], there are few studies that [67]. The reported sensitivity/specificity in detecting invasive candi-
address the genetic relationship between C. albicans isolates from diasis vary among of above-mentioned techniques reaching 77%/85%
human and animal hosts [18]. Phylogenetic analysis of different C. al- for BDG, 58%/93% for Mannan-Ag, and 64%/58% for CA [1]. There-
bicans species isolated from human and animals showed no relevance fore, the sensitivities or specificities of CA, Mannan-Ag, and Mannan-Ab
for species-specific lineages, although some degree of separation was appeared to be insufficient for accurate diagnosis. However, BDG and
found by the nearest-neighbor analysis between human and animal Mannan-Ag may represent effective serum biomarkers based on whe-
isolates [47]. ther a sensitivity-driven or a specificity-driven approach is taken.
Measurement of mannan-Ag and anti-mannan antibodies can be done
by ELISA [67,113] increasing the sensitivity of diagnostic to 83% and
8. Candida biomarkers 86% for Mannan-Ag and Mannan-Ab measurements, respectively [111].
BDG levels were found to be high in bacteremia, disputing the validity
There is an urgent medical need for new diagnostic tools intended to of this biomarker in the diagnostic of invasive fungal disease [2,109].
early detection of invasive Candida infections and for monitoring the Antibodies against synthetic disaccharide fragments of glucans (ALCA)
course of the antifungal therapy. Numerous diagnostic techniques and chitin (ACCA) have been explored as possible biomarkers of in-
[1,135] and non-culture-based detection methods using serological vasive candidiasis. Besides non-invasive markers, serological marker
biomarkers such as anti-mycelium antibodies [Candida albicans germ such as mannan and (1,3)-beta-D-glucan have proved to be valuable for
tube antibody (CAGTA) test], (1 → 3)-β-d-glucan (BDG), mannan an- diagnostic [112,173].
tigen (Mannan-Ag), and anti-mannan antibodies (Mannan-Ab) are

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Fig. 2. Dual life cycle of Candida albicans and its transition as commensal and virulent form. 1) Virulence factors of C. albicans include morphological transition between yeast and
hyphal forms, cell surface expression of adhesins and invasions, biofilm formation, thigmotropism, phenotypic switching and hydrolytic enzyme secretion 2) Sac6 modulates mor-
phogenesis and oxidative stress responses at the transcriptional level 3) Maintained as a commensal by tripartite interaction involving the organism, resident microbiota and immunity of
the host. 4) gap mutant Candida shows defect in hyphae formation. 5) C. albicans can change its genetic pathways underlying resistance to iron reduction in the bloodstream to those
underlying iron toxicity in the gut, these modifications play a functional role in inducing the commensal–pathogenic transition.

Moreover, serial determination of C. albicans strains by CAGTA test only positive in late infection. Urinal or mucosal positive cultures can
and BDG during empirical antifungal treatment has a high sensitivity be seen during systemic infections but do not necessarily detect in-
and high negative predictive value (NPV) in ICU patients with severe vasive candidiasis [48]. Cultures of blood samples collected under
abdominal conditions [91]. If properly used, this method could be ap- sterile conditions have long been accepted as gold standards for diag-
plied to avoid unnecessary antifungal therapy in at least 31% of pa- nosis of invasive candidiasis [36]. Non-culture diagnostic methods,
tients as a complementary approach in antifungal control programs such as detection assays for antibody, antigen, or BDG, and polymerase
[105]. chain reaction (PCR) are recently introduced to clinical practice addi-
The combination of CAGTA and BDG or CAGTA and mannan-Ag had tional to culture-based tests. These approaches can diagnose a much
a very high NPV at the alternative cut-offs and could be used in anti- larger number of patients with invasive candidiasis and lead to better
fungal control programs as an approach for limiting unnecessary em- antifungal treatment decisions. Combining culture and nonculture
pirical therapy in patients with suspected candidemia [104]. Few data methods guide (allow) the clinicians to carefully evaluate the types of
are available on biomarkers in patients suffering from deep-seated invasive candidiasis, assess the limitations and strengths of the tests,
candidiasis with negative blood cultures [184] and lack of individual and consider the test results according to the relevant clinical settings
data may make interpretations difficult, leading to inconclusive out- [138].
comes, and false positive and false negative results [147]. Interestingly, One of the gold standard techniques for the identification of yeast is
a bispecific monoclonal antibody, made up from a combination of a DNA sequencing. However, this approach presents several drawbacks
monoclonal antibody (mAb) directed against BDG with an mAb re- such as the limitations of the currently accepted DNA barcode system
cognizing MP65, a major immunogenic mannoprotein secreted by C. for fungi [167], its cost, the lack of well-trained professionals [48], and
albicans appeared to be an efficient detection tool for clinically -sig- the lack of standard quality controls to confirm the accuracy of mole-
nificant Candida biomarkers in patient sera [204]. cular approaches [196]. Besides, testing the presence of serum BDG in
candidemia appeared to be highly associated with different fungal
9. Diagnosis species, the lowest sensitivity being for C. parapsilosis [114]. Perfor-
mance evaluation of the C. albicans CAGTA, mannan-Ag, mannan-Ab,
Laboratory diagnosis of Candida is complicated because circulating and Candida DNA for diagnosing invasive candidiasis in ICU patients
antibodies to Candida species could be present in normal subjects as an with acute abdominal situations revealed that positive C. albicans
outcome of commensal colonization of mucosal surfaces thereby de- CAGTA and positive BDG in a single blood sample or BDG positivity in
creasing the usefulness of antibody detection for diagnosing candi- two consecutive blood samples represent effective indicators for the
diasis. In addition, antigens derived from different Candida species are colonization of Candida species implicated in invasive candidiasis in
often quickly removed from the circulation and antigen-based diag- severe IAC patients [91]. Moreover, the evaluation of a commercialized
nostic methods often lack sensitivity. Microbiological approval is also real-time polymerase chain reaction (RT-PCR) designed for detecting
complicated considering the fact that blood cultures of up to 50% of DNA derived from C. albicans, C. glabrata, C. dubliniensis, C. parapsilosis,
autopsy-proven cases with deep-seated candidiasis may be negative or C. krusei, C. tropicalis, and C. lusitaniae in milk samples of patients

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suspected to have mammary candidiasis, concluded that RT-PCR was order to recognize the resistant Candida species, enabling formulation
not specific and sensitive enough for diagnosing mammary candidiasis. of guidelines for prevention and control of candidemia in high risk-
But the same assay provided sufficient specificity and sensitivity for the patients [138]. Fluconazole therapy is the most frequent antifungal
detection of C. albicans at an early stage from blood sample [123,125]. treatment inpatients (n = 121) for whom drug usage data were avail-
Recently, a nonculture test named T2 magnetic resonance (T2MR) able [82,152]. Potency and safety of weekly fluconazole was in-
was introduced as a novel method for Candida species. This test can vestigated in women infected with HIV to prevent mucosal candidiasis.
rapidly identify a multiplex of five Candida species in a single blood A 200 mg fluconazole dose was found to be effective and safe in pre-
sample [124,144]. T2MR can detect Candida directly in patient sam- venting oropharyngeal and vaginal candidiasis, but not in esophageal
ples; thereby allowing the accurate and rapid diagnosis of invasive candidiasis. Voriconazole is recommended during neutropenia
candidiasis [144]. This method was applied to improve an automated [139,169]. In addition, the predictive use of fluconazole appeared to be
instrument platform, T2Dx, in order to explore a “patient sample-to- effective for high risk patients [58]. Moreover, a controlled regime of
answer” clinical diagnostic test referred to as T2 Candida panel (cur- fluconazole showed prophylactic effects against Candida infections in
rently accepted by the US Food and Drug Administration). Moreover, patients undergoing bone-marrow transplantation and in hospitalized
various molecular approaches, including a number of DNA-based patients. In case of complications like metastasis, a minimum 2 weeks
techniques such as in-house and commercial polymerase chain reac- duration of therapy is recommended to eliminate the fungal infection
tions, peptide–nucleic acid fluorescence in situ hybridization and ma- from the blood stream [61,97,139].
trix-assisted laser desorption/ionization time-of-flight mass spectro- In vitro antifungal susceptibility to 5-flucytosine (5FC), itraconazole
metry are available [146]. These new advances may replace standard (ITC), amphotericin B (AMB), voriconazole (VRC), caspofungin (CASP),
time-consuming methods often leading to large false negative errors. and fluconazole (FLC) demonstrated that all blood isolates were more
Hyperspectral fluorescence microscopy was reported to detect auto- or lesssusceptible to all evaluated antifungal agents regarding to
fluorescence of Candida species. This fluorescence-based approach can Clinical and Laboratory Standards Institute (CLSI) guidelines (MIC
be used as a diagnostic marker in order to differentiate various Candida range: ≤0.125–1.00 μg/mL for 5FC, ≤0.015–0.125 μg/mL for ITC,
species [63]. This procedure allows an accurate and fast sample analysis 0,125–1.00 μg/mL for AMB, ≤0.015–0.06 μg/mL for VRC,
based on the specific autofluorescence spectra from different Candida ≤0.015–0.125 μg/mL for CASP and ≤0.125–0.5 μg/mL for FLC) [142].
species and showed up to 84% accuracy when conducted in conditions Moreover, caspofungin, a lipopeptide antifungal drug were able to
closely mimicking physiological conditions. A recent outbreak of C. prevent and treat C. albicans biofilms in a murine model implanted with
auris in a London cardiothoracic center between April 2015 and July a central venous catheter [89]. Recently, a synthetic peptide (hLF1-11)
2016 emphasized the importance of the use of new approaches allowing of human lactoferrin (hLF) which is an iron-binding glycoprotein of
a rapid and accurate detection of Candida species in patients in order to 77 kDa produced in mucosal gland epithelial cells, successfully prevent
limit the transmission of hospital-acquired candidiasis infections [165]. C. albicans biofilm formation [122]. Another study demonstrated that
activity of a lipopeptide biosurfactant synthesized by Bacillus subtilis
10. Prevention and control of C. albicans AC7 (AC7 BS) inhibited the formation and adhesion of biofilms on
medical-grade SEDs [30]. Besides, silver nanoparticles represent other
Preventive strategies have proved to be far more effective than the promising inhibitors of C. albicans biofilm formation [88].
cureof Candida infectionss using antifungal agents [106]. Early re- Recently, daily washing of diaper-covered sites with miconazole
sponses of innate immune system by the epithelium, including cyto- soap was found to be effective for the reduction of candidiasis incidence
kines and antimicrobial peptides (AMPs), are important for the pro- in elderly patients hospitalized in long-term inpatient care [181].
tection against fungal overgrowth. Specific AMPs, such as human β-
defensins 1–3, have direct fungicidal activity in primary control of 11. Conclusion and future directions
Candida infection [185]. Probiotics, such as lactic acid bacteria, also
control the formation of C. albicans hyphae in a dose-dependent The incidence of life-threatening fungal infections has been in-
manner, and cause fungicidal acidity at partially higher concentrations creasing over the last 20 years. The major part of these infections are
[50,84,175]. Moreover, a Lactobacillus brevis isolate (CV8LAC) could induced by Candida species, mainly C. albicans. This fungus typically
inhibit C. albicans adhesion and biofilm formation on medical-grade exists as a harmless commensal microorganism in the microflora of the
silicone elastomeric disks (SEDs) [31]. Development of biofilm, fila- oral cavity, skin as well as in the GI and urogenital tracts of warm-
mentation, and intercellular adherence of C. albicans are reportedly blooded animals and most humans. C. albicans is also the fourth most
controlled following interactions between C. albicans and Pseudomonas common type of bloodstream infection exhibiting various virulence,
aeruginosa due to the activity of phenazines produced by P. aeruginosa epidemiology, and susceptibility to antifungals. The study of various
[120]. An experimental model of oral infection revealed that host re- hospital samples from different regions revealed C. albicans as the most
sponses to C. albicans isolates are diverse and interleukin (IL)-17 sig- common isolated species, although the prevalence of non–C.albicans
naling is required for the control of C. albicans infections. IL-17 re- Candida (NACA) species also appeared to be increasing. In addition,
sponse was conserved among isolates, such as those with postponed depending on the sample collection method and the affected tissues, C.
induction of IL-17 [168]. Moreover, interleukin-1 receptor signaling albicans can be detected in up to 70% of the healthy individuals.
plays a significant role in fungal control at the infection onset through Different clusters of C. albicans genotypes responsible for candidemia
its effect on circulating and bone-marrow neutrophils [4]. has been reported in different locations, thereby revealing differences
Echinophora platyloba extract appeared to be efficient in treating in strain transmission. C. albicans has diverse phenotypic and genetic
azole-resistant clinical isolates of C. albicans by effectively reducing forms that lead to polymorphisms, cryptic mating, chromosomal in-
CDR1 and CDR2 expression, which play critical roles in fluconazole versions, copy number variations, recombination, loss of LOH, sub-
resistance in Candida species [79]. Moreover, trypsin inhibitor (TesTI) telomeric hypervariation, and whole or partial chromosome aneu-
from Tecoma stans (yellow elder) was recently investigated for anti- ploidies. The fungus can sense changes in environmental conditions and
Candida activity. It showed antifungal effects against C. albicans and C. adapts its metabolism accordingly. Apart from glucose and other su-
krusei without cytotoxicity at concentrations of 10 and 100 μg/mL gars, uptake of amino acids is very important and has critical roles in
[140]. TesTI stimulates oxidative stress (ATP depletion and lipid per- fungus morphogenesis and virulence.
oxidation) in C. albicans and C. krusei, presumably impairing energy Recently, our understanding of the critical proteins, environmental
metabolism. conditions, cellular and molecular mechanisms that underlie host im-
Testing the sensitivity of Candida spp. to antifungals is necessary in munity against Candida infection has progressed. Identifying multiple

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