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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

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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-

Candida albicans and other emerging NAC species, including
Candida glabrata, Candida krusei, Candida tropicalis, and Candida para-
psilosis represent an important source of systemic infections worldwide.
These organisms are the most common cause of superficial vaginal or
mucosal oral infections and may also, under propitious conditions,
enter the bloodstream leading to deep-tissue infections
[40,186,198,198]. C. albicans is a member of the human microflora as a
diploid polymorphic yeast of mucosal surfaces and is commonly found
in the human gastrointestinal (GI), respiratory, and genitourinary
tracts. It is generally a harmless commensal fungus that can turn into an
opportunistic organism in immunocompromised or immunologically
deficient individuals. With a variety of host cells, including Th17 cell,
this microorganism can interact during the disease manifestations [77].
An abnormal growth in C. albicans due to environmental imbalance like
strated that C. albicans systemic infections lead to a mortality rate of
∼40% [66]. C. albicans is the major species responsible forinvasive
candidiasis (46.3%), followed by C. glabrata (24.4%) and C. parapsilosis
(8.1%) [5]. As a commensal pathogen, Candida can adapt to hosts'
environmental changes very quickly, even when nutrients bioavail-
ability is restricted [116]. The outcomes of C. albicans infections within
the damage response framework can fit into six classifications taking
into account the associated host immune response, the anatomical site
of infection, the Candida virulence; the morphology of hyphae and
hyphae-specific gene expression as critical factors for virulence
[72,183]. Remarkably, the morbidity associated with C. albicans in-
fections mainly depends on the associated host immune responses and
affected tissues/organs. Virulence, epidemiology, and antifungal sus-
ceptibility of all Candida species differ, but the term candidiasis is
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.
ubiquitous yeasts. Since Candida species may superficially colonize
healthy hosts without causing any notable damage, active immune re-
sponses against antigens of Candida can be also detected in im-
munocompetent individuals [27,170].
The most important risk factors for C. albicans infections are anti-
biotic therapy followed by central venous access, surgical procedures,
neutropenia, parenteral nutrition, urinary catheter, as well as some
disease such as hematologic malignancy, solid cancer, prematurity,
cardiac disease, trauma, neurologic disease, gastrointestinal disease,
organ transplant, pulmonary disease, vascular disease, HIV, genetic
disease/congenital malformation, renal disease, diabetes mellitus, liver
disease and pancreatic disease [25]. In severely immunocompromised
individuals, C. albicans induces systemic infection [81] and may turn
from local opportunistic or commensal infections of the mouth, throat,
and reproductive tract to a systemic invasive candidiasis affecting the
circulatory system, bones, and brain [80]. In atopic and allergic in-
dividuals, the chronic exposure to C. albicans act as an aggravating
factor in atopic dermatitis (AD) and lead to the production of specific
immunoglobulin E (IgE) against C. albicans antigens [51,164]. More
recently, C. albicans emerges as a novel pathogenic candidate in bipolar
disorder and schizophrenia [176]. This review highlights the most re-
cent evidences that C. albicans competes out opportunistic pathogens in
invasive candidiasis. We also review important features of candidiasis
regarding its etiology, epidemiology, molecular characterization, and
typing of pathogenic species to improve the diagnostic, prevention and
control of this widespread disease.
2. Etiology and epidemiology of candidiasis
Candida infection is the main cause of nosocomial bloodstream in-
fections (BSIs) in tertiary care hospitals worldwide. The incidence of
candidemia caused by strains that are resistant to fluconazole is high.
Candida spp. are also responsible for chronic infections in the ICU in-
patients and in hospitalized children, leading to important healthcare
costs [55,64,157,179]. Candida species were reportedas the fourth most
common cause of blood-borne microbial infections [85].
Fifteen Candida species can be pathogenic for humans, but more
than 90% of reported invasive candidiasis are associated with the five
most common species i.e. C. albicans, C. glabrata, C. parapsilosis, C.
krusei, and C. tropicalis. Although the recent rise in the number of these
infections [138,186] ismainly associated toC. albicans, NAC-related
diseases are also increasingly reported in different parts of the world
[110]. For example, the vulvovaginal candidiasis (VVC) that affects
millions of women every year is mainly caused by C. albicans, but NAC
species, especially C. glabrata, have been reported as a cause of this
infection [60,200]. The virulence, epidemiology, and susceptibility to
antifungal drugs differ among different pathogenic species responsible
for invasive candidiasis [68,137].
Regarding the intra-abdominal candidiasis (IAC), the most common
type of deep-tissue candidiasis, the antifungal treatment trials and di-
agnostics are not well understood compared to those for candidemia
[9]. Due to the frequently combined infections of Candida with bacteria
and the lack of beneficial antifungal treatments for IAC, the clinical
significance of the presence of Candida spp. in samples cultures from
intra-abdominal tissues remains controversial [118,158,189].
The use of molecular tools has generated a large amount of in-
formation about the biology of Candida. This has enabled the diagnosis
of emerging Candida species using efficient molecular approaches such
as internal transcribed spacer (ITS) sequencing. Polymorphism analysis
of rDNA regions by ITS appeared to be advantageous as a distinguishing
genetic marker in studying molecular phylogenetics and epidemiology,
species identification, and for documenting the natural history of can-
didiasis. This method allowed the identification of emerging Candida
species as a source of hematogenous infections [10,26,29,130]. The
global prevalence of candidemia highly varies in different parts of the
world, ranging from 1.1 to 14.4 out of every 105 cases [6,57,131,134].
129
Microbial Pathogenesis 117 (2018) 128–138
The highest prevalence was reported in the USA [38] where the noso-
comial candidemia represents an important threat [14]. The most im-
portant risk factors for incidence of Candida BSI are parenteral nutri-
tion, broad-spectrum antibiotics, immuno-suppression induced by
radiotherapy or chemotherapy, interruption of mucosal barriers be-
cause of surgery, ICU admission, and indwelling medical devices (e.g.,
central venous catheters) [45,93]. Accurate identification of specific
Candida species could control the risk for nosocomial infections and
exogenous transmission in certain patient populations [180].
Incidence-related risk factors for Candida colonization vary between
C. albicans and NAC. Moreover, oral hygiene, and systemic and living
conditions including dietary uptake of nutrients play critical roles in the
prevalence of both C. albicans and NAC infections among populations of
different countries [13,162]. More than 60% of the Candida isolates
were identified as C. albicans; while NAC was identified in 8.6% of
symptomatic patients and 14.3% of asymptomatic patients [19]. In
young individuals the highest mortality results from infections caused
by general purpose genotype (GPG) of C. albicans.
Another study of patients with invasive candidiasis, documented
from 2011 to 2013 in southwest of China, reported that although C.
albicans was the most frequently isolated Candida species (48.6% of all
invasive candidiasis patients), NAC species were also commonly iso-
lated [149]. In addition, swab samples of vaginal secretion collected
from 200 Iranian patients with clinical VVC revealed that C. albicans
species accounted for 67% of single and mixed infections [151]. Re-
portedly, the prevalence of denture stomatitis due to C. albicans was
relatively significant in a cohort of 2271 infected patient in Iran
reaching 28.9% [119]. Furthermore, many other studies have high-
lighted the importance of C. albicans as the primary pathogen causing
stabilized and exacerbated denture stomatitis in 93% of affected pa-
tients [23]. An epidemiological study of patients admitted to 26 Spanish
hospitals reported that C. albicans was the most common species iso-
lated from patients with invasive candidiasis, even though cases with
NAC infections were apparently increasing [129] (see Table 1).
3. Molecular typing of C. albicans
Molecular typing is an efficient technique used to examine the po-
pulation structure and epidemiological characteristics of fungal pa-
thogens, yielding valuable information on the dynamics of C. albicans
infections in human populations [161]. The assessment of genetic re-
latedness of the organism has become much easier with the spread of
molecular typing methods. This approach allowed the determination of
several clusters for different C. albicans genotypes [16,103].
Multilocus enzyme electrophoresis (MLEE) is based on the differ-
ential electrophoretic mobility of approximately ten enzymes making
possible to achieve reproducible fungal phenotyping outcomes [28].
However, this technique has been widely replaced with restriction
fragment length polymorphism (RFLP) analyses along with electro-
phoretic karyotyping (EK) and random amplified polymorphic DNA
(RAPD) analyses [178]. All these techniques are somewhat limited
because of low inter-laboratory reproducibility of their respective re-
sults. To overcome these limitations, whole-genome DNA sequencing
has l substituted the molecular-typing techniques applied to C. albicans
strains, improving the typing methods through the powerful compar-
ison of DNA sequences [103]. Besides, multilocus sequence typing
(MLST) of C. albicans isolates, based on DNA sequencing of PCR-am-
plified 300–400-bp regions of seven housekeeping genes, and re-
presents a highly reproducible and sensitive technique providing a
discriminatory power compatible with that of Ca3-based fingerprinting.
MLST also represents a valuable method for understanding the popu-
lation structure and epidemiology of systemic Candida infections
[39,132,202]. Comparative studies using MLST are available online on
the curated MLST database of C. albicans (http://calbicans.mlst.net/).
Reportedly, MLST clade 1 is the most common MLST cluster among
related strains of C. albicans. Clade 2 is mainly prevalent in the United
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,
clade 11 includes isolates from continental Europe, while isolates from
the Pacific region belong to a cluster regrouping the clades 14 and 17
[131]. More recently, recovered MLST isolates from bloodstream in-
fections in South Korea have emerged as a novel Asian clade [177].
Molecular fingerprinting of C. albicans did not support intra-hospital
transmission of C. albicans isolated from candidemia patients in Kuwait
[7]. A retrospective single-center study of Candida species distribution
in a hospital located in Mexico City showed that microsatellites re-
present a reliable method for molecular typing and genetic analysis of
Candida isolates. This study reported a clonal population including 62
identified genotypes among the tested isolates [65].
4. C. albicans commensalism and virulence factors
Yeast and hyphal cells are the two most important morphological
forms of C. albicans that condition its virulence [201]. Transition from
yeast to hyphae determines C. albicans commensal and pathogenic
states and may lead to tissue infection, macrophage evasion, host-cell
adhesion, and development of clinically relevant biofilm communities
[190]. Therefore, post-transcriptional mechanisms underlying this
morphological transition control C. albicans virulence processes by in-
fluencing mRNA stability, alternative transcript localization and
translation [75]. Moreover, the C. albicans fibrin Sac6 modulates mor-
phogenesis and oxidative stress responses at the transcriptional level
[203]. Besides, metabolic adaptation is involved in the vulnerability of
C. albicans to antifungal medicines and also influenced key virulence
agents, stress resistance and fungal susceptibility to innate immune
responses [22]. C. albicans is maintained in its commensal form by a
tripartite interaction that involves the organism, resident microbiota
and immunity of the host. The gastro-intestinally induced transition
(GUT) highlights how C. albicans can use distinct genetic pathways for
the transition between commensal and invasive pathogenic states
[128,136] before infecting epithelial cells through two specific me-
chanisms, i.e. active penetration and endocytosis [52,194].
Candida spp. virulence factors include: morphological transition
between yeast and hyphal forms; cell surface expression of adhesins and
invasions; biofilm formation; thigmotropism; phenotypic switching and
hydrolytic enzyme secretion. Many phase-specific genes and hypha-
specific genes express proteins directly or indirectly drive pathogenesis
and virulence of C. albicans [95,107]. These major pathways regulate
expression of hypha-specific and/or phase-specific genes, including the
mitogen-activated protein kinase pathway through Cph1, the cAMP-
dependent protein kinase pathway via Efg1, and Tup1-mediated re-
pression through Rfg1 and Nrg1. Moreover, surface proteins are also
critical in the interactions between the fungal cells and various con-
stitutive or inducible host defense mechanisms that are activated during
candidiasis [174]. For example, the putative NADH-ubiquinone-related
proteins, Ali1, Mci4, Orf19.287, and Orf19.7590, are implicated in
oxidative and osmotic resistance, yeast-to-hypha transition, and the
capability to infect and damage oral epithelial cells [59]. Moreover,
filamentation reportedly protects C. albicans from amphotericin B-in-
duced programmed cell death through a mechanism involving the yeast
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.
C. albicans and its cell-wall β-glucans are able to stimulate monocyte
reprogramming as one of the main immunological responses in infected
hosts [150]. Cheng and his colleagues showed that β-glucan produced
by C. albicans increased the expression of some inflammatory cytokines
upon consequent LPS challenges of infected hosts [33,34]. Moreover,
active pathogen-associated molecular pattern molecules masking by a
Candida species could compromise detection of the fungus by the im-
mune system [8]. Interestingly, interactions between host defense re-
sponses and C. albicans revealed that members of the zinc-cluster-factor
family changes C. albicans virulence [71]. Infections to the C. albicans
strain PCA-2 was accompanied by high number of peripheral blood
polymorphonuclear cells and by activation of spleen cells leading to
highly potent candidacidal effects in vitro [11]. In case of genitourinary
tract infections, the relevant virulence factors were reported as pro-
teinase and phospholipase [187]. Possible species-related differences in
colonization dynamics or pathogenicity of Candida has been proposed
[78]. Moreover, different morphologies of C. albicans undergo certain
interactions with host cells during an infection [37]. It was suggested
that epithelial mechanisms drive mucosal tissues in order to dissociate
the pathogenic and commensal states of C. albicans [155,182]. For ex-
ample, C. albicans cells treated with a medicinal plant extract of Rho-
domyrtus tomentosa, showed adeclined adhesion to surfaces, thereby
inhibiting virulence factors of C. albicans [70].
In addition, phosphate metabolism has been shown to slightly affect
virulence of the different clades of C. albicans [99] while the blocking of
two-component signaling led to elevate the virulence of C. albicans as
an adaptive mechanism interacting with stress-activated protein kinase
[44]. Another study revealed that secreted C. albicans protein Pra1,

130
M. Dadar et al.
which is known as a fungal protease, could disrupt host innate im-
munity through blocking the complement C3 and C3 activation frag-
ments [98].
C. albicans also triggers NLRP3-mediated pyroptosis in macro-
phages enabling them to escape macrophage defenses. Moreover, C.
albicans-infected bone-marrow-derived macrophages and murine J774
macrophages undergo pyroptotic cell death that could be suppressed by
glycine and pharmacological inhibitors of caspase-1 [197].
Alteration of the environmental pH is another mechanism by which
pathogenic fungi defeat the host defenses [192]. Reportedly, C. albicans
has evolved multiple pathways for regulating the pH of host environ-
ments to maintain its virulence [42]. Moreover, C. albicans acidifies the
environment in a carbohydrate-dependent manner, resulting in aspartyl
proteases production, which is an important virulence factor [126]. C.
albicans strains can use amino acids as a carbon source allowing them to
neutralize the acidic environment of the macrophage phagosomes by
signaling through the transcription factor Stp2 [115]. Thus, it has been
shown that the SPS system (abbreviation for the three components of
SSY1, an amino acid transporter homolog, PTR3, peripherally mem-
brane associated protein, and SSY5, a chymotrypsin-like serine en-
doprotease) is critical for resistance of C. albicans to macrophages.
Moreover, the SPS system is stimulated under carbon-source starvation
conditions resembling the host environment modulating by this way the
necessary Stp2 for the catabolism of amino acids and the fungal inter-
actions with innate immune cells [115,116]. Recent studies reported
that metabolism intrudes upon the chromatin for transcriptional control
of macrophage activation [86]. The mechanisms of escaping macro-
phages and immune evasion by C. albicans are depicted in Fig. 1.
5. Genetic instability of C. albicans
C. albicans has significant phenotypic and genetic diversity [41]. It
contains a diploid genome with 14.4 megabases that is arranged as 8
chromosomes [21]. The heterozygosity and heterozygous of genome is
thought to be related with C. albicans virulence [24]. In addition, it is
now well documented that genomic instability of C. albicans play a
major role in its pathogenesis [163]. Also, strain-specific differences of
fungal species may contribute on the interaction of C. albicans and host
[21]. The genetic instability of C. albicans can modulate the candida
behavior at the host interface, the growth rate, the morphology, re-
sistance to stressors including antimicrobial peptides or antifungals and
the fungus pathogenicity during mucosal and systemic infection
[21,168]. For instance, C. albicans can change its genetic pathways
underlying resistance to iron reduction in the bloodstream to those
underlying iron toxicity in the gut during the commensal–pathogenic
transition [32].
There is a non-random distribution of genes over chromosomes of
this microorganism. The C. albicans genome is highly plastic, and
clinical isolates show various karyotypes [35,160]. In response to some
stresses, including heat shock, host–pathogen interactions, and pre-
sence of antifungal drugs, chromosome rearrangements are well toler-
ated in C. albicans [17,54,171]. Genomic plasticity in C. albicans can be
reflected as polymorphisms, cryptic mating, chromosomal inversions,
copy number variations, recombination, loss of heterozygosity (LOH),
subtelomeric hypervariation, and whole or partial chromosome aneu-
ploidies [69,172]. Therefore, phenotypic differences and intraspecies
genetic diversity have been shown to provoke natural mutations that
change the balance between pathogenicity and commensalism in C.
albicans [168]. Moreover, the intraspecies diversity of C. albicans trig-
gers qualitatively and temporally distinct host responses that determine
the balance between commensalism and pathogenicity.
6. The relevance of C. albicans and host nutrient levels
Several important nutritional signals help to regulate morphogen-
esis and pathogenesis during C. albicans infection [76]. The organism
131
Microbial Pathogenesis 117 (2018) 128–138
uses glucose as the preferred carbon source through three anticipated
approaches leading to the transport and metabolism of glucose [159].
The pathways of sugar receptor–repressor include the glucose repres-
sion pathway and the adenylate cyclase pathway. Moreover, C. albicans
uses multiple other carbon sources in the host. During infection of tis-
sues and organs, a signature shift in gene expression is seen towards
using alternative carbon sources through upregulation of other path-
ways, including gluconeogenesis, glyoxylate cycle, and β-oxidation of
fatty acids. Also, mutations in genes responsible for paving pathways
that use alternative carbon sources attenuate virulence and represent
pleiotropic phenotypes in C. albicans [153]. For example, coconut oil
could be used as the first dietary intervention to reduce colonization of
C. albicans in GI [66]. As amino acids are the main source of nitrogen
for C. albicans growth and Gap4, a member of amino acid permease
family, is necessary for S-Adenosylmethionine (SAM)-induced mor-
phogenesis [83].
Studies have shown that in C. albicans there is a close association
between hypoxia and the initiation of hypha formation, especially when
using embedded agar [62]. Different gap mutants that cause changes/
defects in hypha formation and colony morphology of C. albicans were
tested on several solid media to induce morphological changes (Spider,
SLAD, LEE medium, and medium containing N-acetylglucosamine)
[74,90,96,101,154] and a control group as SLD and YNB media con-
taining NH4 was designed. It was found that all investigated strains had
smooth colonies on the control media. Strains such as gap1Δ/gap1Δ
mutant also showed comparable hyphal morphogenesis under hypha-
inducing conditions. For example, a defect in morphogenesis was ob-
served in the Spider medium [12]. Slightly defective hypha formation
was observed only in the GAP3-deletion strain in Spider medium; hy-
phae started to generate two days later when comparedall other dele-
tion or wild-type strains. The same phenotype was reported for three
independent gap3Δ/gap3Δ mutants. In addition, morphogenesis defects
were observed in the gap4Δ/gap4Δ strain on SLD and SAM media. Co-
lonies of this strain were smooth, and they did not grow hyphae even
after seven days of prolonged incubation [83]. Moreover, N-acet-
ylglucosamine-inducible CaGAP1 reportedly expressed a common
amino acid permease regulating morphogenesis and responses to ex-
ternal nitrogen-source in C. albicans [12]. In addition, changing the
carbon source of C. albicans alters virulence in models of systemic
candidiasis and vaginitis, suggesting that alternative carbon sources
within host niches are important during different kinds of infections
with C. albicans [49]. Besides, changes in nutrient bioavailability induce
morphological flexibility and are associated with the deregulation of
glutathione levels and isocitrate lyase activity, reflecting the fact that
preservation of intracellular redox equilibrium is important for the
adaptive metabolism of C. albicans [20,193].
7. Candidiasis in animals
C. albicans is globally distributed in different animals. It is a normal
opportunistic flora of the GI, respiratory tracts, and the external geni-
talia of various animals. All domestic animals, including birds, cattle,
horses, pigs, cats, and dogs are susceptible to Candida infections [47]. C.
albicans causes thrush in domestic poultry, water fowls and wild birds;
mainly affecting upper digestive tract of young birds. Affected birds
revealed pseudomembrane or diphtheritic membranes, and multifocal
to confluent mats of cheesy material in the crop with presence of round
raised ulcers giving a look of ‘Turkish-towel’ in the mucosa. Candida
species induce arthritis in horses [100], and mastitis [53] and abortion
[73] in cattle. Candida species have been reported in urinary tract in-
fections in dogs and cats [148]. Moreover, a case of mycotic en-
dophthalmitis caused by C. albicans has been reported in dogs [94].
Moreover, Candida-induced peritonitis with perforating intestinal le-
sions after surgery have been reported in dogs [133], while mucosal
and cutaneous candidiasis has been demonstrated in im-
munosuppressed [121,195] and diabetic dogs [141]. Using
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
etiological agent in a dog suffering from diffuse cutaneous candidiasis
[121]. Accordingly, all domestic animals could be reservoirs or vectors
for transmission of C. albicans strains causing human candidiasis and
thereby posing a potential risk for immunocompromised patients.
Although, many reports of candidiasis in animals as well as humans
have been documented [108,127,148,156], there are few studies that
address the genetic relationship between C. albicans isolates from
human and animal hosts [18]. Phylogenetic analysis of different C. al-
bicans species isolated from human and animals showed no relevance
for species-specific lineages, although some degree of separation was
found by the nearest-neighbor analysis between human and animal
isolates [47].
8. Candida biomarkers
There is an urgent medical need for new diagnostic tools intended to
early detection of invasive Candida infections and for monitoring the
course of the antifungal therapy. Numerous diagnostic techniques
[1,135] and non-culture-based detection methods using serological
biomarkers such as anti-mycelium antibodies [Candida albicans germ
tube antibody (CAGTA) test], (1 → 3)-β-d-glucan (BDG), mannan an-
tigen (Mannan-Ag), and anti-mannan antibodies (Mannan-Ab) are
available for sensitive and rapiddiagnosis of invasive candidiasis
[92,117,184]. Some of these diagnostic approaches include detection of
Candida DNA and detection of circulating fungal antigens in serum.
Commercial tests are available for detecting and measuring BDG,
Mannan-Ag and Cand-TecTM Candida-antigen (CA); while promising
techniques using nucleic acid amplification have yet to be standardized
[67]. The reported sensitivity/specificity in detecting invasive candi-
diasis vary among of above-mentioned techniques reaching 77%/85%
for BDG, 58%/93% for Mannan-Ag, and 64%/58% for CA [1]. There-
fore, the sensitivities or specificities of CA, Mannan-Ag, and Mannan-Ab
appeared to be insufficient for accurate diagnosis. However, BDG and
Mannan-Ag may represent effective serum biomarkers based on whe-
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
86% for Mannan-Ag and Mannan-Ab measurements, respectively [111].
BDG levels were found to be high in bacteremia, disputing the validity
of this biomarker in the diagnostic of invasive fungal disease [2,109].
Antibodies against synthetic disaccharide fragments of glucans (ALCA)
and chitin (ACCA) have been explored as possible biomarkers of in-
vasive candidiasis. Besides non-invasive markers, serological marker
such as mannan and (1,3)-beta-D-glucan have proved to be valuable for
diagnostic [112,173].

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

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

133
M. Dadar et al.
suspected to have mammary candidiasis, concluded that RT-PCR was
not specific and sensitive enough for diagnosing mammary candidiasis.
But the same assay provided sufficient specificity and sensitivity for the
detection of C. albicans at an early stage from blood sample [123,125].
Recently, a nonculture test named T2 magnetic resonance (T2MR)
was introduced as a novel method for Candida species. This test can
rapidly identify a multiplex of five Candida species in a single blood
sample [124,144]. T2MR can detect Candida directly in patient sam-
ples; thereby allowing the accurate and rapid diagnosis of invasive
candidiasis [144]. This method was applied to improve an automated
instrument platform, T2Dx, in order to explore a “patient sample-to-
answer” clinical diagnostic test referred to as T2 Candida panel (cur-
rently accepted by the US Food and Drug Administration). Moreover,
various molecular approaches, including a number of DNA-based
techniques such as in-house and commercial polymerase chain reac-
tions, peptide–nucleic acid fluorescence in situ hybridization and ma-
trix-assisted laser desorption/ionization time-of-flight mass spectro-
metry are available [146]. These new advances may replace standard
time-consuming methods often leading to large false negative errors.
Hyperspectral fluorescence microscopy was reported to detect auto-
fluorescence of Candida species. This fluorescence-based approach can
be used as a diagnostic marker in order to differentiate various Candida
species [63]. This procedure allows an accurate and fast sample analysis
based on the specific autofluorescence spectra from different Candida
species and showed up to 84% accuracy when conducted in conditions
closely mimicking physiological conditions. A recent outbreak of C.
auris in a London cardiothoracic center between April 2015 and July
2016 emphasized the importance of the use of new approaches allowing
a rapid and accurate detection of Candida species in patients in order to
limit the transmission of hospital-acquired candidiasis infections [165].
10. Prevention and control of C. albicans
Preventive strategies have proved to be far more effective than the
cureof Candida infectionss using antifungal agents [106]. Early re-
sponses of innate immune system by the epithelium, including cyto-
kines and antimicrobial peptides (AMPs), are important for the pro-
tection against fungal overgrowth. Specific AMPs, such as human β-
defensins 1–3, have direct fungicidal activity in primary control of
Candida infection [185]. Probiotics, such as lactic acid bacteria, also
control the formation of C. albicans hyphae in a dose-dependent
manner, and cause fungicidal acidity at partially higher concentrations
[50,84,175]. Moreover, a Lactobacillus brevis isolate (CV8LAC) could
inhibit C. albicans adhesion and biofilm formation on medical-grade
silicone elastomeric disks (SEDs) [31]. Development of biofilm, fila-
mentation, and intercellular adherence of C. albicans are reportedly
controlled following interactions between C. albicans and Pseudomonas
aeruginosa due to the activity of phenazines produced by P. aeruginosa
[120]. An experimental model of oral infection revealed that host re-
sponses to C. albicans isolates are diverse and interleukin (IL)-17 sig-
naling is required for the control of C. albicans infections. IL-17 re-
sponse was conserved among isolates, such as those with postponed
induction of IL-17 [168]. Moreover, interleukin-1 receptor signaling
plays a significant role in fungal control at the infection onset through
its effect on circulating and bone-marrow neutrophils [4].
Echinophora platyloba extract appeared to be efficient in treating
azole-resistant clinical isolates of C. albicans by effectively reducing
CDR1 and CDR2 expression, which play critical roles in fluconazole
resistance in Candida species [79]. Moreover, trypsin inhibitor (TesTI)
from Tecoma stans (yellow elder) was recently investigated for anti-
Candida activity. It showed antifungal effects against C. albicans and C.
krusei without cytotoxicity at concentrations of 10 and 100 μg/mL
[140]. TesTI stimulates oxidative stress (ATP depletion and lipid per-
oxidation) in C. albicans and C. krusei, presumably impairing energy
metabolism.
Testing the sensitivity of Candida spp. to antifungals is necessary in
134
Microbial Pathogenesis 117 (2018) 128–138
order to recognize the resistant Candida species, enabling formulation
of guidelines for prevention and control of candidemia in high risk-
patients [138]. Fluconazole therapy is the most frequent antifungal
treatment inpatients (n = 121) for whom drug usage data were avail-
able [82,152]. Potency and safety of weekly fluconazole was in-
vestigated in women infected with HIV to prevent mucosal candidiasis.
A 200 mg fluconazole dose was found to be effective and safe in pre-
venting oropharyngeal and vaginal candidiasis, but not in esophageal
candidiasis. Voriconazole is recommended during neutropenia
[139,169]. In addition, the predictive use of fluconazole appeared to be
effective for high risk patients [58]. Moreover, a controlled regime of
fluconazole showed prophylactic effects against Candida infections in
patients undergoing bone-marrow transplantation and in hospitalized
patients. In case of complications like metastasis, a minimum 2 weeks
duration of therapy is recommended to eliminate the fungal infection
from the blood stream [61,97,139].
In vitro antifungal susceptibility to 5-flucytosine (5FC), itraconazole
(ITC), amphotericin B (AMB), voriconazole (VRC), caspofungin (CASP),
and fluconazole (FLC) demonstrated that all blood isolates were more
or lesssusceptible to all evaluated antifungal agents regarding to
Clinical and Laboratory Standards Institute (CLSI) guidelines (MIC
range: ≤0.125–1.00 μg/mL for 5FC, ≤0.015–0.125 μg/mL for ITC,
0,125–1.00 μg/mL for AMB, ≤0.015–0.06 μg/mL for VRC,
≤0.015–0.125 μg/mL for CASP and ≤0.125–0.5 μg/mL for FLC) [142].
Moreover, caspofungin, a lipopeptide antifungal drug were able to
prevent and treat C. albicans biofilms in a murine model implanted with
a central venous catheter [89]. Recently, a synthetic peptide (hLF1-11)
of human lactoferrin (hLF) which is an iron-binding glycoprotein of
77 kDa produced in mucosal gland epithelial cells, successfully prevent
C. albicans biofilm formation [122]. Another study demonstrated that
activity of a lipopeptide biosurfactant synthesized by Bacillus subtilis
AC7 (AC7 BS) inhibited the formation and adhesion of biofilms on
medical-grade SEDs [30]. Besides, silver nanoparticles represent other
promising inhibitors of C. albicans biofilm formation [88].
Recently, daily washing of diaper-covered sites with miconazole
soap was found to be effective for the reduction of candidiasis incidence
in elderly patients hospitalized in long-term inpatient care [181].
11. Conclusion and future directions
The incidence of life-threatening fungal infections has been in-
creasing over the last 20 years. The major part of these infections are
induced by Candida species, mainly C. albicans. This fungus typically
exists as a harmless commensal microorganism in the microflora of the
oral cavity, skin as well as in the GI and urogenital tracts of warm-
blooded animals and most humans. C. albicans is also the fourth most
common type of bloodstream infection exhibiting various virulence,
epidemiology, and susceptibility to antifungals. The study of various
hospital samples from different regions revealed C. albicans as the most
common isolated species, although the prevalence of non–C.albicans
Candida (NACA) species also appeared to be increasing. In addition,
depending on the sample collection method and the affected tissues, C.
albicans can be detected in up to 70% of the healthy individuals.
Different clusters of C. albicans genotypes responsible for candidemia
has been reported in different locations, thereby revealing differences
in strain transmission. C. albicans has diverse phenotypic and genetic
forms that lead to polymorphisms, cryptic mating, chromosomal in-
versions, copy number variations, recombination, loss of LOH, sub-
telomeric hypervariation, and whole or partial chromosome aneu-
ploidies. The fungus can sense changes in environmental conditions and
adapts its metabolism accordingly. Apart from glucose and other su-
gars, uptake of amino acids is very important and has critical roles in
fungus morphogenesis and virulence.
Recently, our understanding of the critical proteins, environmental
conditions, cellular and molecular mechanisms that underlie host im-
munity against Candida infection has progressed. Identifying multiple
M. Dadar et al.
mechanisms and understanding the importance of the epithelial cells in
host defense will pave the way to understand the complicated network
of interactions between host and fungus at mucosal surfaces.
Remarkably, some of these mechanisms appear to enable the host to
distinguish between the C. albicans commensalism and pathogenicity.
The laboratory-based diagnosis of Candida is still a complicated process.
The specificity of PCR is questionable when the burden of the fungus is
limited. Therefore, development of accurate diagnostic methods and
novel tools for a rapid and accurate detection of Candida species is
needed. Recent studies suggest that future researches and clinical per-
spectives will support important developments in translational diag-
nostic methods and clinical applications to treat and control Candida
infections. Regarding complementary and alternative therapies, natural
products as well as medicinal plants are promising and exhibit lesser
side effects in comparison to allopathic drugs. However, more efforts
are required to characterize, standardize and commercialize high
quality natural products to cure Candidiasis.
Funding
This compilation is a review article written, analyzed and designed
by its authors and required no substantial funding to be stated.
Conflicts of interest
All authors declare that there exist no commercial or financial re-
lationships that could in any way lead to a potential conflict of interest.
Acknowledgement
All the authors acknowledge and thank their respective Institutes
and Universities.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://dx.
doi.org/10.1016/j.micpath.2018.02.028.
References
[1] S. Ahmad, Z. Khan, Invasive candidiasis: a review of nonculture-based laboratory
diagnostic methods, Indian J. Med. Microbiol. 30 (2012) 264–269.
[2] O. Albert, D. Toubas, C. Strady, J. Cousson, C. Delmas, V. Vernet, I. Villena,
Reactivity of (1→ 3)-β-d-glucan assay in bacterial bloodstream infections, Eur. J.
Clin. Microbiol. Infect. Dis. 30 (2011) 1453–1460.
[3] B. Almirante, D. Rodríguez, B.J. Park, M. Cuenca-Estrella, A.M. Planes, M. Almela,
J. Mensa, F. Sanchez, J. Ayats, M. Gimenez, P. Saballs, Epidemiology and pre-
dictors of mortality in cases of Candida bloodstream infection: results from po-
pulation-based surveillance, Barcelona, Spain, from 2002 to 2003, J. Clin.
Microbiol. 43 (2005) 1829–1835.
[4] S. Altmeier, A. Toska, F. Sparber, A. Teijeira, C. Halin, S. Leibundgut-Landmann,
IL-1 coordinates the neutrophil response to C. Albicans in the oral mucosa, PLoS
Pathog. 12 (2016) e1005882.
[5] D.R. Andes, N. Safdar, J.W. Baddley, B. Alexander, L. Brumble, A. Freifeld,
S. Hadley, L. Herwaldt, C. Kauffman, G.M. Lyon, The epidemiology and outcomes
of invasive Candida infections among organ transplant recipients in the United
States: results of the Transplant-Associated Infection Surveillance Network
(TRANSNET), Transpl. Infect. Dis. 18 (2016) 921–931.
[6] M.C. Arendrup, Epidemiology of invasive candidiasis, Curr. Opin. Crit. Care 16
(2010) 445–452.
[7] M. Asadzadeh, S. Ahmad, N. Al-Sweih, Z. Khan, Molecular fingerprinting studies
do not support intrahospital transmission of Candida albicans among candidemia
patients in Kuwait, Front. Microbiol. 8 (2017) 247.
[8] E.R. Ballou, G.M. Avelar, D.S. Childers, J. Mackie, J.M. Bain, J. Wagener,
S.L. Kastora, M.D. Panea, S.E. Hardison, L.A. Walker, Lactate signalling regulates
fungal β-glucan masking and immune evasion, Nat. Microbiol. 2 (2016) 16238.
[9] M. Bassetti, M. Marchetti, A. Chakrabarti, S. Colizza, J. Garnacho-Montero,
D.H. Kett, P. Munoz, F. Cristini, A. Andoniadou, P. Viale, A research agenda on the
management of intra-abdominal candidiasis: results from a consensus of multi-
national experts, Intensive Care Med. 39 (2013) 2092–2106.
[10] J. Berman, P.E. Sudbery, Candida albicans: a molecular revolution built on lessons
from budding yeast, Nat. Rev. Genet. 3 (2002) 918–930.
[11] F. Bistoni, A. Vecchiarelli, E. Cenci, P. Puccetti, P. Marconi, A. Cassone, Evidence
135
Microbial Pathogenesis 117 (2018) 128–138
for macrophage-mediated protection against lethal Candida albicans infection,
Infect. Immun. 51 (1986) 668–674.
[12] S. Biswas, M. Roy, A. Datta, N-acetylglucosamine-inducible CaGAP1 encodes a
general amino acid permease which co-ordinates external nitrogen source re-
sponse and morphogenesis in Candida albicans, Microbiology 149 (2003)
2597–2608.
[13] S. Biswas, P. Van dijck, A. Datta, Environmental sensing and signal transduction
pathways regulating morphopathogenic determinants of Candida albicans,
Microbiol. Mol. Biol. Rev. 71 (2007) 348–376.
[14] S.I. Blot, K.H. Vandewoude, E.A. Hoste, F.A. Colardyn, Effects of nosocomial
candidemia on outcomes of critically ill patients, Am. J. Med. 113 (2002)
480–485.
[15] G.P. Bodey, M. Mardani, H.A. Hanna, M. Boktour, J. Abbas, E. Girgawy,
R.Y. Hachem, D.P. Kontoyiannis, Raad II, The epidemiology of Candida glabrata
and Candida albicans fungemia in immunocompromised patients with cancer, Am.
J. Med. 112 (2002) 380–385.
[16] P.S. Bonfim-Mendonca, A. Fiorini, C.S. Shinobu-Mesquita, L.C. Baeza,
M.A. Fernandez, T.I.E. Svidzinski, Molecular typing of Candida albicans isolates
from hospitalized patients, Rev. Inst. Med. Trop. Sao Paulo 55 (2013) 385–391.
[17] K. Bouchonville, A. Forche, K.E. Tang, A. Selmecki, J. Berman, Aneuploid chro-
mosomes are highly unstable during DNA transformation of Candida albicans,
Eukaryot. Cell 8 (2009) 1554–1566.
[18] M.-E. Bougnoux, D.M. Aanensen, S. Morand, M. Théraud, B.G. Spratt, C. D’enfert,
Multilocus sequence typing of Candida albicans: strategies, data exchange and
applications, Infect. Genet. Evol. 4 (2004) 243–252.
[19] T.M. Brandolt, G.B. Klafke, C.V. Gonçalves, L.R. Bitencourt, A.M.B. De Martinez,
J.F. Mendes, M.C.A. Meireles, M.O. Xavier, Prevalence of Candida spp. in cervical-
vaginal samples and the in vitro susceptibility of isolates, Braz. J. Microbiol. 48
(2017) 145–150.
[20] C. Braunsdorf, D. Mailänder-Sánchez, M. Schaller, Fungal sensing of host en-
vironment, Cell Microbiol. 18 (2016) 1188–1200.
[21] C. Braunsdorf, S. LeibundGut-Landmann, Modulation of the fungal-host interac-
tion by the intra-species diversity of C. Albicans, Pathogens 7 (2018) 11.
[22] A.J. Brown, G.D. Brown, M.G. Netea, N.A. Gow, Metabolism impacts upon
Candida immunogenicity and pathogenicity at multiple levels, Trends Microbiol.
22 (2014) 614–622.
[23] E. Budtz-Jörgensen, A. Stenderup, M. Grabowski, An epidemiologic study of yeasts
in elderly denture wearers, Community Dent. Oral Epidemiol. 3 (1975) 115–119.
[24] G. Butler, M.D. Rasmussen, M.F. Lin, M.A. Santos, S. Sakthikumar, C.A. Munro,
E. Rheinbay, M. Grabherr, A. Forche, J.L. Reedy, I. Agrafioti, Evolution of pa-
thogenicity and sexual reproduction in eight Candida genomes, Nature 459 (2009)
657–662.
[25] H.M.S. Canela, B. Cardoso, L.H. Vitali, H.C. Coelho, R. Martinez, M.E.D.S. Ferreira,
Prevalence, virulence factors and antifungal susceptibility of Candida spp. isolated
from bloodstream infections in a tertiary care hospital in Brazil, Mycoses 61
(2018) 11–21.
[26] P.L. Carlisle, M. Banerjee, A. Lazzell, C. Monteagudo, J.L. Lopez-Ribot, D. Kadosh,
Expression levels of a filament-specific transcriptional regulator are sufficient to
determine Candida albicans morphology and virulence, Proc. Natl. Acad. Sci. U. S.
A 106 (2009) 599–604.
[27] A. Casadevall, Antibody-mediated protection against intracellular pathogens,
Trends Microbiol. 6 (1998) 102–107.
[28] D.A. Caugant, P. Sandven, Epidemiological analysis of Candida albicans strains by
multilocus enzyme electrophoresis, J. Clin. Microbiol. 31 (1993) 215–220.
[29] E. Cendejas-Bueno, A. Gomez-Lopez, E. Mellado, J.L. Rodriguez-Tudela,
M. Cuenca-Estrella, Identification of pathogenic rare yeast species in clinical
samples: comparison between phenotypical and molecular methods, J. Clin.
Microbiol. 48 (2010) 1895–1899.
[30] C. Ceresa, M. Rinaldi, V. Chiono, I. Carmagnola, G. Allegrone, L. Fracchia,
Lipopeptides from Bacillus subtilis AC7 inhibit adhesion and biofilm formation of
Candida albicans on silicone, Antonie Leeuwenhoek 109 (2016) 1375–1388.
[31] C. Ceresa, F. Tessarolo, I. Caola, G. Nollo, M. Cavallo, M. Rinaldi, L. Fracchia,
Inhibition of Candida albicans adhesion on medical-grade silicone by a
Lactobacillus-derived biosurfactant, J. Appl. Microbiol. 118 (2015) 1116–1125.
[32] C. Chen, K. Pande, S.D. French, B.B. Tuch, S.M. Noble, An iron homeostasis reg-
ulatory circuit with reciprocal roles in Candida albicans commensalism and pa-
thogenesis, Cell Host Microbe 10 (2011) 118–135.
[33] S.-C. Cheng, L.A.B. Joosten, B.-J. Kullberg, M.G. Netea, Interplay between Candida
albicans and the mammalian innate host defense, Infect. Immun. 80 (2012)
1304–1313.
[34] S.-C. Cheng, J. Quintin, R.A. Cramer, K.M. Shepardson, S. Saeed, V. Kumar,
E.J. Giamarellos-Bourboulis, J.H. Martens, N.A. Rao, A. Aghajanirefah, mTOR-and
HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity,
Science 345 (2014) 1250684.
[35] H. Chibana, J.L. Beckerman, P. Magee, Fine-resolution physical mapping of
genomic diversity in Candida albicans, Genome Res. 10 (2000) 1865–1877.
[36] C.J. Clancy, M.H. Nguyen, Finding the “missing 50%” of invasive candidiasis: how
nonculture diagnostics will improve understanding of disease spectrum and
transform patient care, Clin. Infect. Dis. 56 (2013) 1284–1292.
[37] I.A. Cleary, S.M. Reinhard, A.L. Lazzell, C. Monteagudo, D.P. Thomas, J.L. Lopez-
Ribot, S.P. Saville, Examination of the pathogenic potential of Candida albicans
filamentous cells in an animal model of haematogenously disseminated candi-
diasis, FEMS Yeast Res. 16 (2016) fow011.
[38] A.A. Cleveland, L.H. Harrison, M.M. Farley, R. Hollick, B. Stein, T.M. Chiller,
S.R. Lockhart, B.J. Park, Declining incidence of candidemia and the shifting epi-
demiology of Candida resistance in two US metropolitan areas, 2008–2013: results
M. Dadar et al.
from population-based surveillance, PLoS One 10 (2015) e0120452.
[39] P.R. Cliff, J.A. Sandoe, J. Heritage, R.C. Barton, Use of multilocus sequence typing
for the investigation of colonisation by Candida albicans in intensive care unit
patients, J. Hosp. Infect. 69 (2008) 24–32.
[40] H.R. Conti, A.R. Huppler, N. Whibley, S.L. Gaffen, Animal models for candidiasis,
Curr. Protoc. Im. 105 (2014) 19.6.1–19.6.17.
[41] C. D’enfert, M.-E. Bougnoux, A. Feri, M. Legrand, R. Loll-Krippleber, T. Marton,
C. Maufrais, J. Ropars, N. Sertour, E. Sitterlé, Genome Diversity and Dynamics in
Candida Albicans. Candida Albicans: Cellular and Molecular Biology, Springer,
2017.
[42] H.A. Danhof, S. Vylkova, E.M. Vesely, A.E. Ford, M. Gonzalez-Garay, M.C. Lorenz,
Robust Extracellular pH Modulation by Candida albicans during growth in car-
boxylic acids, mBio 7 (2016) e01646–16.
[43] P. Datta, M. Kaur, S. Gombar, J. Chander, Epidemiology and antifungal suscept-
ibility of Candida species isolated from urinary tract infections: a study from an
intensive care unit of a tertiary care hospital, Indian J. Crit. Care Med. 22
(2018) 56.
[44] A.M. Day, D.A. Smith, M.A. Ikeh, M. Haider, C.M. Herrero-De-Dios, A.J. Brown,
B.A. Morgan, L.P. Erwig, D.M. Maccallum, J. Quinn, Blocking two-component
signalling enhances Candida albicans virulence and reveals adaptive mechanisms
that counteract sustained SAPK activation, PLoS Pathog. 13 (2017) e1006131.
[45] G. Dimopoulos, F. Ntziora, G. Rachiotis, A. Armaganidis, M.E. Falagas, Candida
albicans versus non-albicans intensive care unit-acquired bloodstream infections:
differences in risk factors and outcome, Anesth. Analg. 106 (2008) 523–529.
[46] A.M. Doi, A.C.C. Pignatari, M.B. Edmond, A.R. Marra, L.F.A. Camargo,
R.A. Siqueira, V.P. da Mota, A.L. Colombo, Epidemiology and microbiologic
characterization of nosocomial candidemia from a Brazilian national surveillance
program, PLoS One 11 (2016) p.e0146909.
[47] A. Edelmann, M. Krüger, J. Schmid, Genetic relationship between human and
animal isolates of Candida albicans, J. Clin. Microbiol. 43 (2005) 6164–6166.
[48] A. Ellepola, C.J. Morrison, Laboratory diagnosis of invasive candidiasis, J.
Microbiol. 43 (2005) 65–84.
[49] I.V. Ene, A.K. Adya, S. Wehmeier, A.C. Brand, D.M. Maccallum, N.A. Gow,
A.J. Brown, Host carbon sources modulate cell wall architecture, drug resistance
and virulence in a fungal pathogen, Cell Microbiol. 14 (2012) 1319–1335.
[50] M.E. Falagas, G.I. Betsi, S. Athanasiou, Probiotics for prevention of recurrent
vulvovaginal candidiasis: a review, J. Antimicrob. Chemother. 58 (2006)
266–272.
[51] J. Faergemann, Atopic dermatitis and fungi, Clin. Microbiol. Rev. 15 (2002)
545–563.
[52] S.G. Filler, Candida–host cell receptor–ligand interactions, Curr. Opin. Microbiol.
9 (2006) 333–339.
[53] G. Foley, D. Schlafer, Candida abortion in cattle, Vet. Pathol. 24 (1987) 532–536.
[54] A. Forche, P. Magee, A. Selmecki, J. Berman, G. May, Evolution in Candida albicans
populations during a single passage through a mouse host, Genetics 182 (2009)
799–811.
[55] S.K. Fridkin, D. Kaufman, J.R. Edwards, S. Shetty, T. Horan, Changing incidence of
Candida bloodstream infections among NICU patients in the United States:
1995–2004, An. Pediatr. 117 (2006) 1680–1687.
[56] J. Fu, Y. Ding, B. Wei, L. Wang, S. Xu, P. Qin, L. Wei, L. Jiang, Epidemiology of
Candida albicans and non-C. albicans of neonatal candidemia at a tertiary care
hospital in western China, BMC Infect. Dis. 17 (2017) 329.
[57] M. Gamaletsou, T.J. Walsh, T. Zaoutis, M. Pagoni, M. Kotsopoulou, M. Voulgarelis,
P. Panayiotidis, T. Vassilakopoulos, M. Angelopoulou, M. Marangos, A pro-
spective, cohort, multicentre study of candidaemia in hospitalized adult patients
with haematological malignancies, Clin. Microbiol. Infect. 20 (2014) O50–O57.
[58] J. Garbino, D.P. Lew, J.-A. Romand, S. Hugonnet, R. Auckenthaler, D. Pittet,
Prevention of severe Candida infections in nonneutropenic, high-risk, critically ill
patients: a randomized, double-blind, placebo-controlled trial in patients treated
by selective digestive decontamination, Intensive Care Med. 28 (2002)
1708–1717.
[59] A. Gil-Bona, C.M. Parra-Giraldo, M.L. Hernáez, J.A. Reales-Calderon, N.V. Solis,
S.G. Filler, L. Monteoliva, C. Gil, Candida albicans cell shaving uncovers new
proteins involved in cell wall integrity, yeast to hypha transition, stress response
and host–pathogen interaction, J. Proteomics 127 (2015) 340–351.
[60] B. Gonçalves, C. Ferreira, C.T. Alves, M. Henriques, J. Azeredo, S. Silva,
Vulvovaginal candidiasis: epidemiology, microbiology and risk factors, Crit. Rev.
Microbiol. 42 (2016) 905–927.
[61] J.L. Goodman, D.J. Winston, R.A. Greenfield, P.H. Chandrasekar, B. Fox,
H. Kaizer, R.K. Shadduck, T.C. Shea, P. Stiff, D.J. Friedman, A controlled trial of
fluconazole to prevent fungal infections in patients undergoing bone marrow
transplantation, N. Engl. J. Med. 326 (1992) 845–851.
[62] N. Grahl, K.M. Shepardson, D. Chung, R.A. Cramer, Hypoxia and fungal patho-
genesis: to air or not to air? Eukaryot. Cell 11 (2012) 560–570.
[63] M.S. Graus, A.K. Neumann, J.A. Timlin, Hyperspectral fluorescence microscopy
detects autofluorescent factors that can be exploited as a diagnostic method for
Candida species differentiation, J. Biomed. Optic. 22 (2017) 016002–016002.
[64] O. Gudlaugsson, S. Gillespie, K. Lee, J.V. Berg, J. Hu, S. Messer, L. Herwaldt,
M. Pfaller, D. Diekema, Attributable mortality of nosocomial candidemia, re-
visited, Clin. Infect. Dis. 37 (2003) 1172–1177.
[65] H.T. Guerrero, I.M. Espinosa, M.G. Ibarra, M.A. García, Distribution of Candida
species and molecular typing of C. Albicans isolates in a Mexico city tertiary care
hospital from 2011 to 2013, Open J. Med. Microbiol. 6 (2016) 66.
[66] K.T. Gunsalus, S.N. Tornberg-Belanger, N.R. Matthan, A.H. Lichtenstein,
C.A. Kumamoto, Manipulation of host diet to reduce gastrointestinal colonization
by the opportunistic pathogen Candida albicans, mSphere 1 (2016) e00020–15.
136
Microbial Pathogenesis 117 (2018) 128–138
[67] J. Held, I. Kohlberger, E. Rappold, A.B. Grawitz, G. Häcker, Comparison of (1→ 3)-
β-D-Glucan, mannan/anti-mannan-antibodies and cand-tec Candida-Antigen as
serum biomarkers for candidemia, J. Clin. Microbiol. (2013) JCM-02473-12.
[68] J.A. Hill, R. Ammar, D. Torti, C. Nislow, L.E. Cowen, Genetic and genomic ar-
chitecture of the evolution of resistance to antifungal drug combinations, PLoS
Genet. 9 (2013) e1003390.
[69] M.P. Hirakawa, D.A. Martinez, S. Sakthikumar, M.Z. Anderson, A. Berlin, S. Gujja,
Q. Zeng, E. Zisson, J.M. Wang, J.M. Greenberg, Genetic and phenotypic intra-
species variation in Candida albicans, Genome Res. 25 (2015) 413–425.
[70] J. Hmoteh, K.S. Musthafa, S.P. Voravuthikunchai, Effects of Rhodomyrtus to-
mentosa extract on virulence factors of Candida albicans and human neutrophil
function, Arch. Oral Biol. 87 (2018) 35–42.
[71] L. Issi, R.A. Farrer, K. Pastor, B. Landry, T. Delorey, G.W. Bell, D.A. Thompson,
C.A. Cuomo, R.P. Rao, Members of the zinc cluster factor family alters virulence in
Candida albicans, Genetics 116 (2016) 195024.
[72] M.A. Jabra-Rizk, E.F. Kong, C. Tsui, M.H. Nguyen, C.J. Clancy, P.L. Fidel,
M. Noverr, Candida albicans pathogenesis: fitting within the host-microbe damage
response framework, Infect. Immun. 84 (2016) 2724–2739.
[73] H. Jensen, H. Krogh, H. Schønheyder, Bovine mycotic abortion—a comparative
study of diagnostic methods, Zoonoses Public Health 38 (1991) 33–40.
[74] M.A. Kabir, M.A. Hussain, Z. Ahmad, Candida albicans: A model organism for
studying fungal pathogens, ISRN Microbiol. 2012 (2012).
[75] D. Kadosh, Control of Candida albicans morphology and pathogenicity by post-
transcriptional mechanisms, Cell. Mol. Life Sci. 73 (2016) 4265–4278.
[76] D. Kadosh, J.L. Lopez-Ribot, Candida albicans: adapting to succeed, Cell Host
Microbe 14 (2013) 483–485.
[77] S.W. Kashem, B.Z. Igyártó, M. Gerami-Nejad, Y. Kumamoto, J. Mohammed,
E. Jarrett, R.A. Drummond, S.M. Zurawski, G. Zurawski, J. Berman, Candida al-
bicans morphology and dendritic cell subsets determine T helper cell differentia-
tion, Immunity 42 (2015) 356–366.
[78] R. Khatib, L.B. Johnson, M.G. Fakih, K. Riederer, L. Briski, Current trends in
candidemia and species distribution among adults: Candida glabrata surpasses C.
albicans in diabetic patients and abdominal sources, Mycoses 59 (2016) 781–786.
[79] E. Khajeh, S.J. Hosseini Shokouh, M. Rajabibazl, M. Roudbary, S. Rafiei, P. Aslani,
Z. Farahnejad, Antifungal effect of Echinophora platyloba on expression of CDR1
and CDR2 genes in fluconazole-resistant Candida albicans, Br. J. Biomed. Sci. 73
(2016) 44–48.
[80] J. Kim, P. Sudbery, Candida albicans, a major human fungal pathogen, J.
Microbiol. 49 (2011) 171.
[81] R.S. Klein, C.A. Harris, C.B. Small, B. Moll, M. Lesser, G.H. Friedland, Oral can-
didiasis in high-risk patients as the initial manifestation of the acquired im-
munodeficiency syndrome, N. Engl. J. Med. 311 (1984) 354–358.
[82] W. Knitsch, J.-L. Vincent, S. Utzolino, B. François, T. Dinya, G. Dimopoulos,
İ. Özgüneş, J.C. Valía, P. Eggimann, C. León, A randomized, placebo-controlled
trial of pre-emptive antifungal therapy for the prevention of invasive candidiasis
following gastrointestinal surgery for intra-abdominal infections, Clin. Infect. Dis.
61 (2015) 1671–1678.
[83] L. Kraidlova, S. Schrevens, H. Tournu, G. Van Zeebroeck, H. Sychrova, P. Van
Dijck, Characterization of the Candida albicans amino acid permease family: gap2
is the only general amino acid permease and Gap4 is an S-Adenosylmethionine
(SAM) transporter required for SAM-induced morphogenesis, mSphere 1 (2016)
e00284–16.
[84] S. Kumar, A. Bansal, A. Chakrabarti, S. Singhi, Evaluation of efficacy of probiotics
in prevention of Candida colonization in a PICU—a randomized controlled trial,
Crit. Care Med. 41 (2013) 565–572.
[85] M. Lackner, M. Tscherner, M. Schaller, K. Kuchler, C. Mair, B. Sartori, F. Istel,
M. Arendrup, C. Lass-Flörl, Positions and numbers of FKS mutations in Candida
albicans selectively influence in vitro and in vivo susceptibilities to echinocandin
treatment, Antimicrob. Agents Chemother. 58 (2014) 3626–3635.
[86] P.K. Langston, M. Shibata, T. Horng, Metabolism supports macrophage activation,
Front. Immunol. 8 (2017).
[87] D.J. Laprade, M.S. Brown, M.L. Mccarthy, J.J. Ritch, N. Austriaco, Filamentation
protects Candida albicans from amphotericin B-induced programmed cell death via
a mechanism involving the yeast metacaspase, MCA1, Microb. Cell 3 (2016) 285.
[88] H.H. Lara, D.G. Romero-Urbina, C. Pierce, J.L. Lopez-Ribot, M.J. Arellano-
Jiménez, M. Jose-Yacaman, Effect of silver nanoparticles on Candida albicans
biofilms: an ultrastructural study, J. Nanobiotechnol. 13 (2015) 91.
[89] A.L. Lazzell, A.K. Chaturvedi, C.G. Pierce, D. Prasad, P. Uppuluri, J.L. Lopez-Ribot,
Treatment and prevention of Candida albicans biofilms with caspofungin in a
novel central venous catheter murine model of candidiasis, J. Antimicrob.
Chemother. 64 (2009) 567–570.
[90] K. Lee, H.R. Buckley, C.C. Campbell, An amino acid liquid synthetic medium for
the development of mycellal and yeast forms of Candida albicans, J. Med. Vet.
Mycol. 13 (1975) 148–153.
[91] C. León, S. Ruiz-Santana, P. Saavedra, C. Castro, A. Loza, I. Zakariya, A. Úbeda,
M. Parra, D. Macías, J.I. Tomás, Contribution of Candida biomarkers and DNA
detection for the diagnosis of invasive candidiasis in ICU patients with severe
abdominal conditions, Crit. Care 20 (2016) 149.
[92] C. León, S. Ruiz-Santana, P. Saavedra, C. Castro, A. Úbeda, A. Loza, E. Martín-
Mazuelos, A. Blanco, V. Jerez, J. Ballús, Value of β-D-glucan and Candida albicans
germ tube antibody for discriminating between Candida colonization and invasive
candidiasis in patients with severe abdominal conditions, Intensive Care Med. 38
(2012) 1315–1325.
[93] O. Leroy, J.-P. Gangneux, P. Montravers, J.-P. Mira, F. Gouin, J.-P. Sollet, J. Carlet,
J. Reynes, M. Rosenheim, B. Regnier, Epidemiology, management, and risk factors
for death of invasive Candida infections in critical care: a multicenter, prospective,
M. Dadar et al.
observational study in France (2005–2006), Crit. Care Med. 37 (2009) 1612–1618.
[94] J. Linek, Mycotic endophthalmitis in a dog caused by Candida albicans, Vet.
Ophthalmol. 7 (2004) 159–162.
[95] H. Liu, Co-regulation of pathogenesis with dimorphism and phenotypic switching
in Candida albicans, a commensal and a pathogen, Int. J. Med. Microbiol. 292
(2002) 299–311.
[96] H. Liu, J. Kohler, G.R. Fink, Suppression of hyphal formation in Candida albicans
by mutation of a STE12 homolog, Science 266 (1994) 1723.
[97] N.-N. Liu, J.R. Köhler, Antagonism of fluconazole and a proton pump inhibitor
against Candida albicans, Antimicrob. Agents Chemother. 60 (2016) 1145–1147.
[98] S. Luo, P. Dasari, N. Reiher, A. Hartmann, S. Jacksch, E. Wende, D. Barz,
M.J. Niemiec, I. Jacobsen, N. Beyersdorf, T. Hünig, The secreted Candida albicans
protein Pra1 disrupts host defense by broadly targeting and blocking complement
C3 and C3 activation fragments, Mol. Immunol. 93 (2018) 266–277.
[99] D.M. Maccallum, L. Castillo, K. Nather, C.A. Munro, A.J. Brown, N.A. Gow,
F.C. Odds, Property differences among the four major Candida albicans strain
clades, Eukaryot. Cell 8 (2009) 373–387.
[100] J. Madison, B. Reid, R. Raskin, Amphotericin B treatment of Candida arthritis in
two horses, J. Am. Vet. Med. Assoc. 206 (1995) 338–341.
[101] M. Maidan, J. Thevelein, P. Van Dijck, Carbon Source Induced Yeast-to-hypha
Transition in Candida Albicans Is Dependent on the Presence of Amino Acids and
on the G-protein-coupled Receptor Gpr1, Portland Press Limited, 2005.
[103] L. Marcos-Zambrano, P. Escribano, M. Sanguinetti, E.G.G. De La Pedrosa, E. De
Carolis, A. Vella, R. Cantón, E. Bouza, J. Guinea, Clusters of patients with candi-
daemia due to genotypes of Candida albicans and Candida parapsilosis: differences
in frequency between hospitals, Clin. Microbiol. Infect. 21 (2015) 677–683.
[104] M.C. Martínez-Jiménez, P. Muñoz, M. Valerio, R. Alonso, C. Martos, J. Guinea,
E. Bouza, Candida biomarkers in patients with candidaemia and bacteraemia, J.
Antimicrob. Chemother. 70 (2015) 2354–2361.
[105] M.C. Martínez-Jiménez, P. Muñoz, M. Valerio, A. Vena, J. Guinea, E. Bouza,
Combination of Candida biomarkers in patients receiving empirical antifungal
therapy in a Spanish tertiary hospital: a potential role in reducing the duration of
treatment, J. Antimicrob. Chemother. 70 (2015) 3107–3115.
[106] N. Martins, I.C. Ferreira, L. Barros, S. Silva, M. Henriques, Candidiasis: predis-
posing factors, prevention, diagnosis and alternative treatment, Mycopathologia
177 (2014) 223–240.
[107] F.L. Mayer, D. Wilson, B. Hube, Candida albicans pathogenicty mechanisms,
Virulence 4 (2013) 119–128.
[108] N. Mcewan, Malassezia and Candida infections in bull terriers with lethal acro-
dermatitis, J. Small Anim. Pract. 42 (2001) 291–297.
[109] M.A. Mennink-Kersten, D. Ruegebrink, P.E. Verweij, Pseudomonas aeruginosa as a
cause of 1, 3-β-d-glucan assay reactivity, Clin. Infect. Dis. 46 (2008) 1930–1931.
[110] K.B. Merseguel, A.S. Nishikaku, A.M. Rodrigues, A.C. Padovan, R.C. E Ferreira,
A.S. De Azevedo Melo, M.R. Da Silva Briones, A.L. Colombo, Genetic diversity of
medically important and emerging Candida species causing invasive infection,
BMC Infect. Dis. 15 (2015) 57.
[111] M. Mikulska, T. Calandra, M. Sanguinetti, D. Poulain, C. Viscoli, The use of
mannan antigen and anti-mannan antibodies in the diagnosis of invasive candi-
diasis: recommendations from the Third European Conference on Infections in
Leukemia, Crit. Care 14 (2010) R222.
[112] M. Mikulska, E. Furfaro, V. Del Bono, F. Gualandi, M.T. Van Lint, F. Miletich,
A. Baciqalupo, C. Viscoli, Persistence of a positive (1,3)-beta-D-glucan test after
clearance of candidemia in hematopoietic stem cell transplant recipients, Clin.
Vaccine Immunol. 18 (2011) 518–519.
[113] M. Mikulska, E. Furfaro, C. Viscoli, Biomarkers for diagnosis and follow-up of
invasive Candidiasis: a brief review of the ECIL recommendations, Curr. Fungal
Infect. Rep. 6 (2012) 192–197.
[114] M. Mikulska, D. Giacobbe, E. Furfaro, A. Mesini, A. Marchese, V. Del Bono,
C. Viscoli, Lower sensitivity of serum (1, 3)-β-d-glucan for the diagnosis of can-
didaemia due to Candida parapsilosis, Clin. Microbiol. Infect. 22 (646) (2016)
e5–646. e8.
[115] P. Miramón, M.C. Lorenz, The SPS amino acid sensor mediates nutrient acquisition
and immune evasion in Candida albicans, Cell Microbiol. 18 (2016) 1611–1624.
[116] P. Miramón, M.C. Lorenz, A feast for Candida: metabolic plasticity confers an edge
for virulence, PLoS Pathog. 13 (2017) e1006144.
[117] J.F. Mohr, C. Sims, V. Paetznick, J. Rodriguez, M.A. Finkelman, J.H. Rex,
L. Ostrosky-Zeichner, Prospective survey of (1→ 3)-β-d-glucan and its relationship
to invasive candidiasis in the surgical intensive care unit setting, J. Clin. Microbiol.
49 (2011) 58–61.
[118] P. Montravers, O. Leroy, C. Eckmann, Intra-abdominal Candidiasis: It's Still a Long
Way to Get Unquestionable Data, Springer, 2015.
[119] M. Moosazadeh, M. Akbari, R. Tabrizi, A. Ghorbani, A. Golkari, M. Banakar,
Denture stomatitis and Candida albicans in iranian population: a systematic re-
view and meta-analysis, J. Dent. 17 (2016) 283.
[120] D.K. Morales, N. Grahl, C. Okegbe, L.E. Dietrich, N.J. Jacobs, D.A. Hogan, Control
of Candida albicans metabolism and biofilm formation by Pseudomonas aeruginosa
phenazines, mBio 4 (2013) e00526–12.
[121] A. Moretti, B. Posteraro, L. Boncio, L. Mechelli, E. Gasperis, F. Agnetti, M. Raspa,
Diffuse cutaneous candidiasis in a dog. Diagnosis by PCR-REA, Rev. Iberoam. De.
Micol. 21 (2004) 139–142.
[122] P. Morici, R. Fais, C. Rizzato, A. Tavanti, A. Lupetti, Inhibition of Candida albicans
biofilm formation by the synthetic lactoferricin derived peptide hLF1, PLoS One
11 (2016) e0167470.
[123] W. Mutschlechner, D. Karall, C. Hartmann, B. Streiter, S. Baumgartner-Sigl,
D. Orth-Höller, C. Lass-Flörl, Mammary candidiasis: molecular-based detection of
Candida, Eur. J. Clin. Microbiol. Infect. Dis. 35 (2016) 1309–1313.
137
Microbial Pathogenesis 117 (2018) 128–138
[124] E. Mylonakis, C.J. Clancy, L. Ostrosky-Zeichner, K.W. Garey, G.J. Alangaden,
J.A. Vazquez, J.S. Groeger, M.A. Judson, Y.-M. Vinagre, S.O. Heard, T2 magnetic
resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical
trial, Clin. Infect. Dis. (2015) 959.
[125] M. Nabili, M. Ashrafi, G. Janbabaie, M.T. Hedayati, K. Ali-Moghaddam,
T. Shokohi, Quantification and optimization of Candida albicans DNA in blood
samples using Real-Time PCR, Rep. Biochem. Mol. Biol. 2 (2013) 42–47.
[126] J.R. Naglik, S.J. Challacombe, B. Hube, Candida albicans secreted aspartyl pro-
teinases in virulence and pathogenesis, Microbiol. Mol. Biol. Rev. 67 (2003)
400–428.
[127] J.R. Naglik, P.L. Fidel Jr., F.C. Odds, Animal models of mucosal Candida infection,
FEMS Microbiol. Immunol. 283 (2008) 129–139.
[128] B.A. Neville, C. D'enfert, M.E. Bougnoux, Candida albicans commensalism in the
gastrointestinal tract, FEMS Yeast Res. 15 (2015) fov081.
[129] M. Nieto, O. Tellería, R. Cisterna, Sentinel surveillance of invasive candidiasis in
Spain: epidemiology and antifungal susceptibility, Diagn. Microbiol. Infect. Dis. 81
(2015) 34–40.
[130] F.C. Odds, Molecular phylogenetics and epidemiology of Candida albicans, Future
Microbiol. 5 (2010) 67–79.
[131] F.C. Odds, M.-E. Bougnoux, D.J. Shaw, J.M. Bain, A.D. Davidson, D. Diogo,
M.D. Jacobsen, M. Lecomte, S.-Y. Li, A. Tavanti, Molecular phylogenetics of
Candida albicans, Eukaryot. Cell 6 (2007) 1041–1052.
[132] F.C. Odds, M.D. Jacobsen, Multilocus sequence typing of pathogenic Candida
species, Eukaryot. Cell 7 (2008) 1075–1084.
[133] R.K. Ong, A.L. Raisis, K.L. Swindells, Candida albicans peritonitis in a dog, J. Vet.
Emerg. Crit. Care 20 (2010) 143–147.
[134] A. Osmanov, D.W. Denning, Burden of serious fungal infections in Ukraine,
Mycoses 58 (2015) 94–100.
[135] L. Ostrosky-Zeichner, P.G. Pappas, S. Shoham, A. Reboli, M.A. Barron, C. Sims,
C. Wood, J.D. Sobel, Improvement of a clinical prediction rule for clinical trials on
prophylaxis for invasive candidiasis in the intensive care unit, Mycoses 54 (2011)
46–51.
[136] K. Pande, C. Chen, S.M. Noble, Passage through the mammalian gut triggers a
phenotypic switch that promotes Candida albicans commensalism, Nat. Genet. 45
(2013) 1088–1091.
[137] P.G. Pappas, C.A. Kauffman, D. Andes, D.K. Benjamin, T.F. Calandra, J.E. Edwards,
S.G. Filler, J.F. Fisher, B.-J. Kullberg, L.O. Zeichner, Clinical practice guidelines for
the management candidiasis: 2009 update by the Infectious Diseases Society of
America, Clin. Infect. Dis. 48 (2009) 503–535.
[138] P.G. Pappas, C.A. Kauffman, D.R. Andes, C.J. Clancy, K.A. Marr, L. Ostrosky-
Zeichner, A.C. Reboli, M.G. Schuster, J.A. Vazquez, T.J. Walsh, Clinical practice
guideline for the management of candidiasis: 2016 update by the Infectious
Diseases Society of America, Clin. Infect. Dis. (2015) civ933.
[139] P.G. Pappas, C.A. Kauffman, D.R. Andes, C.J. Clancy, K.A. Marr, L. Ostrosky-
Zeichner, A.C. Reboli, M.G. Schuster, J.A. Vazquez, T.J. Walsh, T.E. Zaoutis,
J.D. Sobel, Executive summary: clinical practice guideline for the management of
candidiasis: 2016 update by the infectious diseases society of America, Clin. Infect.
Dis. 62 (2016) 409–417.
[140] L.L. Patriota, T.F. Procópio, M.F. De Souza, A.P.S. De Oliveira, L.V. Carvalho,
M.G. Pitta, M.J. Rego, P.M. Paiva, E.V. Pontual, T.H. Napoleão, A trypsin inhibitor
from tecoma stans leaves inhibits growth and promotes ATP depletion and lipid
peroxidation in Candida albicans and Candida krusei, Front. Microbiol. 7 (2016).
[141] H. Peikes, D.O. Morris, R.S. Hess, Dermatologic disorders in dogs with diabetes
mellitus: 45 cases (1986–2000), J. Am. Vet. Med. Assoc. 219 (2001) 203–208.
[142] I.H. Peron, F. Reichert-Lima, A.F. Busso-Lopes, C.K. Nagasako, L. Lyra,
M.L. Moretti, A.Z. Schreiber, Resistance surveillance in Candida albicans: a five-
year antifungal susceptibility evaluation in a brazilian University hospital, PLoS
One 11 (2016) e0158126.
[143] M.A. Pfaller, D.J. Diekema, Epidemiology of invasive candidiasis: a persistent
public health problem, Virulence 2 (2007) 119–128.
[144] M.A. Pfaller, D.M. Wolk, T.J. Lowery, T2MR and T2Candida: novel technology for
the rapid diagnosis of candidemia and invasive candidiasis, Future Microbiol. 11
(2016) 103–117.
[145] M.A. Pfaller, D.R. Andes, D.J. Diekema, D.L. Horn, A.C. Reboli, C. Rotstein,
B. Franks, N.E. Azie, Epidemiology and outcomes of invasive candidiasis due to
non-albicans species of Candida in 2,496 patients: data from the Prospective
Antifungal Therapy (PATH) registry 2004–2008, PLoS One 9 (2014) p.e101510.
[146] P. Phoompoung, M. Chayakulkeeree, Recent progress in the diagnosis of patho-
genic Candida species in blood culture, Mycopathologia 181 (2016) 363–369.
[147] J. Pontón, A. Del Palacio, Advances and limitations in the early diagnosis of in-
vasive yeast infections, Rev. Iberoam. De. Micol. 24 (2007) 181–186.
[148] B.M. Pressler, S.L. Vaden, I.F. Lane, L.D. Cowgill, J.A. Dye, Candida spp. urinary
tract infections in 13 dogs and seven cats: predisposing factors, treatment, and
outcome, J. Am. Anim. Hosp. Assoc. 39 (2003) 263–270.
[149] S. Pu, S. Niu, C. Zhang, X. Xu, M. Qin, S. Huang, L. Zhang, Epidemiology, anti-
fungal susceptibilities, and risk factors for invasive candidiasis from 2011 to 2013
in a teaching hospital in southwest China, J. Microbiol. Immunol. Infect. 1 (2017)
97–103.
[150] J. Quintin, S. Saeed, J.H. Martens, E.J. Giamarellos-Bourboulis, D.C. Ifrim,
C. Logie, L. Jacobs, T. Jansen, B.-J. Kullberg, C. Wijmenga, Candida albicans in-
fection affords protection against reinfection via functional reprogramming of
monocytes, Cell Host Microbe 12 (2012) 223–232.
[151] M.M. Rad, S. Zafarghandi, B. Abbasabadi, M. Tavallaee, The epidemiology of
Candida species associated with vulvovaginal candidiasis in an Iranian patient
population, Eur. J. Obstet. Gynecol. Reprod. Biol. 155 (2011) 199–203.
[152] R. Rajendran, L. Sherry, A. Deshpande, E.M. Johnson, M.F. Hanson, C. Williams,
M. Dadar et al.
C.A. Munro, B.L. Jones, G. Ramage, A prospective surveillance study of candi-
daemia: epidemiology, risk factors, antifungal treatment and outcome in hospi-
talized patients, Front. Microbiol. 7 (2016).
[153] M.A. Ramírez, M.C. Lorenz, Mutations in alternative carbon utilization pathways
in Candida albicans attenuate virulence and confer pleiotropic phenotypes,
Eukaryot. Cell 6 (2007) 280–290.
[154] K.H. Rao, S. Ghosh, K. Natarajan, A. Datta, N-acetylglucosamine kinase, HXK1 is
involved in morphogenetic transition and metabolic gene expression in Candida
albicans, PLoS One 8 (2013) e53638.
[155] T.J. Rast, A.L. Kullas, P.J. Southern, D.A. Davis, Human epithelial cells dis-
criminate between commensal and pathogenic interactions with Candida albicans,
PLoS One 11 (2016) e0153165.
[156] L. Reilly, J. Palmer, Systemic candidiasis in four foals, J. Am. Vet. Med. Assoc. 205
(1994) 464–466.
[157] A.M. Rentz, M.T. Halpern, R. Bowden, The impact of candidemia on length of
hospital stay, outcome, and overall cost of illness, Clin. Infect. Dis. 27 (1998)
781–788.
[158] J.H. Rex, Candida in the peritoneum: passenger or pathogen? Crit. Care Med. 34
(2006) 902–903.
[159] J. Sabina, V. Brown, Glucose sensing network in Candida albicans: a sweet spot for
fungal morphogenesis, Eukaryot. Cell 8 (2009) 1314–1320.
[160] E. Rustchenko, Chrosome instability in Candida albicans, FEMS Yeast Res. 7 (2007)
2–11.
[161] F. Saghrouni, J. Ben Abdeljelil, J. Boukadida, M. Ben Said, Molecular methods for
strain typing of Candida albicans: a review, J. Appl. Microbiol. 114 (2013)
1559–1574.
[162] T. Sato, M. Kishi, M. Suda, K. Sakata, H. Shimoda, H. Miura, A. Ogawa,
S. Kobayashi, Prevalence of Candida albicans and non-albicans on the tongue dorsa
of elderly people living in a post-disaster area: a cross-sectional survey, BMC Oral
Health 17 (2017) 51.
[163] S. Satpati, K. Manohar, N. Acharya, A. Dixit, Comparative molecular dynamics
studies of heterozygous open reading frames of DNA polymerase eta (η) in pa-
thogenic yeast Candida albicans, Sci. Rep. 7 (2017).
[164] J. Savolainen, K. Lammintausta, K. Kalimo, M. Viander, Candida albicans and
atopic dermatitis, Clin. Exp. Allergy 23 (1993) 332–339.
[165] S. Schelenz, F. Hagen, J.L. Rhodes, A. Abdolrasouli, A. Chowdhary, A. Hall,
L. Ryan, J. Shackleton, R. Trimlett, J.F. Meis, First hospital outbreak of the
globally emerging Candida auris in a European hospital, Antimicrob. Resist. Infect.
Contr. 5 (2016) 35.
[167] C.L. Schoch, K.A. Seifert, S. Huhndorf, V. Robert, J.L. Spouge, C.A. Levesque,
W. Chen, E. Bolchacova, K. Voigt, P.W. Crous, Nuclear ribosomal internal tran-
scribed spacer (ITS) region as a universal DNA barcode marker for Fungi, Proc.
Natl. Acad. Sci. U.S.A. 109 (2012) 6241–6246.
[168] F. Schönherr, F. Sparber, F. Kirchner, E. Guiducci, K. Trautwein-Weidner,
A. Gladiator, N. Sertour, U. Hetzel, G. Le, N. Pavelka, The intraspecies diversity of
C. albicans triggers qualitatively and temporally distinct host responses that de-
termine the balance between commensalism and pathogenicity, Mucosal
Immunol. (2017), http://dx.doi.org/10.1038/mi.2017.2.
[169] P. Schuman, L. Capps, G. Peng, J. Vazquez, W. El-Sadr, A.I. Goldman, B. Alston,
C.L. Besch, A. Vaughn, M.A. Thompson, Weekly fluconazole for the prevention of
mucosal candidiasis in women with HIV Infection A randomized, double-blind,
placebo-controlled trial, Ann. Intern. Med. 126 (1997) 689–696.
[170] J. Schulze, U. Sonnenborn, Yeast in the Gut: from commensals to infectious agents,
Dtsch. Arzteblatt 106 (2009) 837–842.
[171] A. Selmecki, A. Forche, J. Berman, Aneuploidy and isochromosome formation in
drug-resistant Candida albicans, Science 313 (2006) 367–370.
[172] A. Selmecki, A. Forche, J. Berman, Genomic plasticity of the human fungal pa-
thogen Candida albicans, Eukaryot. Cell 9 (2010) 991–1008.
[173] B. Sendid, N. Dotan, S. Nseir, C. Savaux, P. Vandewalle, A. Standaert, F. Zerimech,
B. Guery, A. Dukler, J. Colombel, Antibodies against glucan, chitin, and
Saccharomyces cerevisiae mannan as new biomarkers of Candida albicans infection
that complement tests based on C. albicans mannan, Clin. Vaccine Immunol. 15
(2008) 1868–1877.
[174] J.-M. Senet, Candida adherence phenomena, from commensalism to pathogeni-
city, Int. Microbiol. 1 (2010) 117–122.
[175] C. Seneviratne, L. Samaranayake, T. Ohshima, N. Maeda, L. Jin, Identification of
antifungal molecules from novel probiotic Lactobacillus bacteria for control of
Candida infection, Hong Kong Med. J. 22 (2016).
[176] E.G. Severance, K.L. Gressitt, C.R. Stallings, E. Katsafanas, L.A. Schweinfurth,
C.L. Savage, M.B. Adamos, K.M. Sweeney, A.E. Origoni, S. Khushalani, Candida
albicans exposures, sex specificity and cognitive deficits in schizophrenia and bi-
polar disorder, NPJ Schizophr. 2 (2016) 16018.
[177] J.H. Shin, M.-E. Bougnoux, C. D'enfert, S.H. Kim, C.-J. Moon, M.Y. Joo, K. Lee, M.-
N. Kim, H.S. Lee, M.G. Shin, Genetic diversity among Korean Candida albicans
bloodstream isolates: assessment by multilocus sequence typing and restriction
endonuclease analysis of genomic DNA by use of BssHII, J. Clin. Microbiol. 49
(2011) 2572–2577.
[178] D.R. Soll, The ins and outs of DNA fingerprinting the infectious fungi, Clin.
138
View publication stats
Microbial Pathogenesis 117 (2018) 128–138
Microbiol. Rev. 13 (2000) 332–370.
[179] W.J. Steinbach, Pediatric invasive candidiasis: epidemiology and diagnosis in
children, J. Fungi 2 (2016) 5.
[180] G. Suleyman, G.J. Alangaden, Nosocomial fungal infections: epidemiology, in-
fection control, and prevention, Infect. Dis. Clin. North Am. 30 (2016) 1023–1052.
[181] H. Takahashi, N. Oyama, I. Tanaka, M. Hasegawa, K. Hirano, C. Shimada,
M. Hasegawa, Preventive effects of topical washing with miconazole nitrate-con-
taining soap to diaper candidiasis in hospitalized elderly patients: a prospective,
double-blind, placebo-controlled study, J. Dermatol. 7 (2017) 760–766.
[182] S. Tang, D. Moyes, J. Richardson, M. Blagojevic, J. Naglik, Epithelial discrimina-
tion of commensal and pathogenic Candida albicans, Oral Dis. 22 (2016) 114–119.
[183] D.S. Thompson, P.L. Carlisle, D. Kadosh, Coevolution of morphology and virulence
in Candida species, Eukaryot. Cell 10 (2011) 1173–1182.
[184] F. Tissot, F. Lamoth, P.M. Hauser, C. Orasch, U. Flückiger, M. Siegemund,
S. Zimmerli, T. Calandra, J. Bille, P. Eggimann, β-Glucan antigenemia anticipates
diagnosis of blood culture–negative intraabdominal candidiasis, Am. J. Respir.
Crit. Care Med. 188 (2013) 1100–1109.
[185] J. Tomalka, E. Azodi, H.P. Narra, K. Patel, S. O’neill, C. Cardwell, B.A. Hall,
J.M. Wilson, A.G. Hise, β-Defensin 1 plays a role in acute mucosal defense against
Candida albicans, J. Immunol. 194 (2015) 1788–1795.
[186] S.A. Turner, G. Butler, The Candida pathogenic species complex, Cold Spring Harb
Perspect Med. (2014), http://dx.doi.org/10.1101/cshperspect.a019778.
[187] Udayalaxmi, S. Jacob, D. D’souza, Comparison between virulence factors of
Candida albicans and non-albicans species of Candida isolated from genitourinary
tract, J. Clin. Diagn. Res. 8 (2014) DC15–DC17.
[188] J.A. Vazquez, V. Sanchez, C. Dmuchowski, L.M. Dembry, J.D. Sobel, M.J. Zervos,
Nosocomial acquisition of Candida albicans: an epidemiologic study, JJ. Infect.
Dis. 168 (1) (1993 Jul 1) 195–201.
[189] P. Vergidis, C.J. Clancy, R.K. Shields, S.Y. Park, B.N. Wildfeuer, R.L. Simmons,
M.H. Nguyen, Intra-abdominal candidiasis: the importance of early source control
and antifungal treatment, PLoS One 11 (2016) e0153247.
[190] J. Verma-Gaur, A. Traven, Post-transcriptional gene regulation in the biology and
virulence of Candida albicans, Cell Microbiol. 18 (2016) 800–806.
[191] C. Viscoli, C. Girmenia, A. Marinus, L. Collette, P. Martino, B. Vandercam,
C. Doyen, B. Lebeau, D. Spence, V. Krcmery, B. De Pauw, Candidemia in cancer
patients: a prospective, multicenter surveillance study by the invasive fungal in-
fection group (IFIG) of the European organization for research and treatment of
cancer (EORTC), Clin. Infect. Dis. 28 (5) (1999 May 1) 1071–1079.
[192] S. Vylkova, Environmental pH modulation by pathogenic fungi as a strategy to
conquer the host, PLoS Pathog. 13 (2017) e1006149.
[193] S. Vylkova, M.C. Lorenz, Phagosomal neutralization by the fungal pathogen
Candida albicans induces macrophage pyroptosis, Infect. Immun. IAI. 85 (2016)
e00832-16.
[194] B. Wächtler, F. Citiulo, N. Jablonowski, S. Förster, F. Dalle, M. Schaller, D. Wilson,
B. Hube, Candida albicans-epithelial interactions: dissecting the roles of active
penetration, induced endocytosis and host factors on the infection process, PLoS
One 7 (2012) e36952.
[195] M. Waxverlem, Cutaneous candidiasis in dog caused by Candida guilliermondii,
Vet. Rec. (2002) 728.
[196] P. Wayne, Interpretive criteria for identification of bacteria and fungi by DNA
target sequencing, Approved Guideline. CLSI Document MM18-A, Clinical and
Laboratory Standards Institute, Wayne, PA, 2008, pp. 26–30 Identification of
Coagulase-Negative Staphylococci.
[197] M. Wellington, K. Koselny, F.S. Sutterwala, D.J. Krysan, Candida albicans triggers
NLRP3-mediated pyroptosis in macrophages, Eukaryot. Cell 13 (2014) 329–340.
[198] S.G. Whaley, E.L. Berkow, J.M. Rybak, A.T. Nishimoto, K.S. Barker, P.D. Rogers,
Azole antifungal resistance in Candida albicans and emerging non-albicans
Candida species, Front. Microbiol. 7 (2017) 2173.
[199] W.L. Whelan, D.R. Kirsch, K.J. Kwon-Chung, S.M. Wahl, P.D. Smith, Candida al-
bicans in patients with the acquired immunodeficiency syndrome: absence of a
novel or hypervirulent strain, J. Infect. Dis. 162 (1990) 513–518.
[200] D.J. White, A. Vanthuyne, Vulvovaginal candidiasis, Sex. Transm. Infect. 82
(Suppl 4) (2006) iv28–iv30.
[201] D. Wilson, J.R. Naglik, B. Hube, The missing link between Candida albicans hyphal
morphogenesis and host cell damage, PLoS Pathog. 12 (2016) e1005867.
[202] K. Wu, T. Luo, L. Li, Q. Zhang, J. Zhu, Q. Gao, M. Chen, M. Zhu, Multilocus se-
quence typing of pathogenic Candida albicans isolates collected from a teaching
hospital in Shanghai, China: a molecular epidemiology study, PLoS One 10 (2015)
e0125245.
[203] B. Zhang, Q. Yu, Y. Wang, C. Xiao, J. Li, D. Huo, D. Zhang, C. Jia, M. Li, The
Candida albicans fimbrin Sac6 regulates oxidative stress response (OSR) and
morphogenesis at the transcriptional level, BBA-Mol. Cell Res. 1863 (2016)
2255–2266.
[204] A. Zito, C. Bromuro, G. Mandili, P. Chiani, A.L. Horenstein, F. Malavasi, R. Cauda,
A. Cassone, A. Torosantucci, A murine, bispecific monoclonal antibody simulta-
neously recognizing β-glucan and mp65 determinants in Candida species, PLoS
One 11 (2016) e0148714.