European Journal of Clinical Microbiology & Infectious Diseases

https://doi.org/10.1007/s10096-020-03912-w

REVIEW

Mechanism of Candida pathogenesis: revisiting the vital drivers

Ifeanyi Elibe Mba 1 & Emeka Innocent Nweze 1

Received: 11 March 2020 / Accepted: 17 April 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Candida is the most implicated fungal pathogen in the clinical setting. Several factors play important roles in the pathogenesis of
Candida spp. Multiple transcriptional circuits, morphological and phenotypic switching, biofilm formation, tissue damaging
extracellular hydrolytic enzymes, metabolic flexibility, genome plasticity, adaptation to environmental pH fluctuation, robust
nutrient acquisition system, adherence and invasions (mediated by adhesins and invasins), heat shock proteins (HSPs), cytolytic
proteins, escape from phagocytosis, evasion from host immune system, synergistic coaggregation with resident microbiota,
resistance to antifungal agents, and the ability to efficiently respond to multiple stresses are some of the major pathogenic
determinants of Candida species. The existence of multiple connections, in addition to the interactions and associations among
all of these factors, are distinctive features that play important roles in the establishment of Candida infections. This review
describes all the underlying factors and mechanisms involved in Candida pathogenesis by evaluating pathogenic determinants of
Candida species. It reinforces the already available pool of data on the pathogenesis of Candida species by providing a clear and
simplified understanding of the most important factors implicated in the pathogenesis of Candida species. The Candida path-
ogenesis network, an illustration linking all the major determinants of Candida pathogenesis, is also presented. Taken together,
they will further improve our current understanding of how these factors modulate virulence and consequent infection(s).
Development of new antifungal drugs and better therapeutic approaches to candidiasis can be achieved in the near future with
continuing progress in the understanding of the mechanisms of Candida pathogenesis.

Keywords Candida . Pathogenesis . Virulence . Fungi . Infections

Introduction
Candida is a diploid fungus that frequently causes mucosal
and systemic infections in humans. The organism exists as a
normal flora in both humans and animals but can become
opportunistic causing disabling and lethal infections [1].
Candida species can colonize several distinct anatomical sites.
Majority of infections by commensal microorganisms come
from endogenous colonization. However, exogenous contam-
ination, such as infections transmitted via hospital employees,
hospital atmosphere, and biofilm-contaminated invasive de-
vices like catheters, can also occur [2–4]. Infections caused
by Candida can be classified as superficial, cutaneous, muco-
sal, and systemic infection (deep and widespread). When
Candida spp. infect the oral cavity, skin, genitalia, respiratory
* Emeka Innocent Nweze
emeka.nweze@unn.edu.ng
1
Department of Microbiology, University of Nigeria, Nsukka, Nigeria
system, and the rest of the gastrointestinal tract, the infection is
classified as the superficial type. Invasive candidiasis is an
infection characterized with extremely severe conditions such
as candidemia (affecting the blood), meningitis (affecting the
brain), and endocarditis (affecting the heart) [5]. In hospital-
ized patients and those with dilapidated immune system, in-
vasive infection is a significant cause of morbidity and mor-
tality with high incidence and prevalence rates.
Candida species pathogenesis is a multifaceted process in-
volving multiple mechanisms and pathways. It is also a com-
plex and multifactorial mechanism, involving features of both
the host and the microorganism [6]. For infection to be
established, the opportunistic pathogen must evade, multiply
in the host environment, and survive in the immune system of
the host. The organism must also be able to disseminate to
other body tissues and organs, most especially in systemic
infection [7]. Disruption of skin or gastrointestinal barriers
can lead to disseminated or deep organ candidiasis. In more
serious situations, blood stream invasion may occur which
subsequently will disseminate to different organs of the body.
Candida infections in most people are asymptomatic. This is

due to the ability of the immunological system to checkmate
the organism as it attempts to spread in the body. However,
depletion in immune system or changes in microbiota balance,
coupled with other factors, can facilitate the spread of
Candida which is often fatal in 42% of reported cases [8–10].
While Candida albicans is responsible for about 50% of
candidiasis, non-albicans Candida species are responsible for
the remainder of the Candida infection. Infection caused by
Candida tropicalis, Candida glabrata, Candida parapsilosis,
Candida krusei, Candida dubliniensis, and Candida auris are
of great concern. Some of these non-albicans Candida species
are now regarded as emerging opportunistic pathogens [11].
Preventing Candida infections mostly caused by Candida spe-
cies is a growing challenge in human medicine. Even with the
availability and use of antifungal medication, disseminated can-
didiasis is accompanied with high mortality rate (about 40–
60%), poor diagnosis, and inappropriate disease management.
The general clinical presentation of the patient also contributes
to the increase in mortality rate. Resistance to antifungal drugs
is no longer a new issue. Even among individuals that have not
been exposed to antibiotics, resistance has been reported [12].
Currently, Candida is one of the leading causes of mucosal
infections in healthy individuals. It also causes systemic/life-
threatening infections especially in immunosuppressive patients,
despite its status as a commensal microorganism [13]. In fact,
candidiasis is considered the third to fourth most common infec-
tion in healthcare facilities within the USA and even globally
[14]. Not surprisingly, it is the virulence and pathogenic attributes
and mechanisms that have received the most attention from re-
searchers over the years. Recently, much have been learned about
the mechanisms of Candida pathogenesis. Studies have shown
that at the heart of the ability of Candida to proliferate, switch
from non-virulence commensal to opportunistic pathogenic fun-
gus and establish infection in the host lie highly interconnected
factors composed of transcriptional circuits, morphology-associ-
ated/virulence encoding genes, metabolic plasticity, genome
plasticity, phenotypic switching, biofilm formation, tissue dam-
aging extracellular hydrolytic enzymes, and several other factors
that facilitate virulence and pathogenesis in Candida species
[15]. Changes in environmental pH, robust nutrient acquisition
system, escape from phagocytosis, evasion from host immune
system, host microbiome coaggregation, resistance to antifungal
agents, and the ability to efficiently respond to multiple stresses
are other vital attributes that enhance survival and pathogenesis.
The existence of multiple connections among all the factors that
aid the establishment of infections is a distinctive feature in the
pathogenesis of Candida species. In this review, we concisely
describe and bring together all the underlying factors and mech-
anisms of Candida pathogenesis with emphasis on the most vital
aspects of Candida pathogenesis. Information presented here
gives a clear, simplified, and general understanding of all the
major factors implicated in the pathogenesis of Candida species.
Development of appropriate preventive and therapeutic
Eur J Clin Microbiol Infect Dis
measures, in addition to curbing Candida infections, is largely
dependent on our understanding of its pathogenesis.
Review methodology
This review was exclusively based on a thorough literature re-
view on the mechanisms of Candida pathogenesis with empha-
sis on the virulence and pathogenic determinants. The Boolean
search for relevant literatures was performed in Google scholar,
Science direct, PubMed, and Web of science using a combina-
tion of the following precise keywords: mechanism of Candida
pathogenesis, virulence factors in Candida species (hyphae
formation/morphology associated genes, biofilm formation, met-
abolic flexibility, phenotypic switching, interaction with resident
microbiota, candidalysin, extracellular hydrolytic enzymes (se-
cretory aspartyl proteinase, lipase, phospholipase, hemolysins
and coagulase), heat shock proteins, pH fluctuation, stress re-
sponse, antifungal resistance and adherence to surfaces). All
the papers that relate to virulent determinants and mechanism
of pathogenesis of Candida species were included in the study.
Pathogenicity of Candida species
The pathogenicity of C. albicans is related to its change be-
tween the commensal yeast form and the invasive hyphal
shape [16]. Upon host cell attachment, thigmotropism (contact
sensing) triggers Candida albicans filamentation. This per-
mits the organism to penetrate deeper into the host tissues
through extracellular enzyme secretion [17]. The ability of
Candida to convert from yeast to hyphae phase or hyphae to
yeast phase is termed dimorphism. Each of these phases of
growth is vital for virulence and pathogenicity as it influences
how Candida escapes the immune system. Yeast and filament
(hyphae) forms play independent roles during disseminated
candidiasis. While the yeast form is involved in dissemination,
the hyphal (filamentous) form is involved in tissue invasion
and pathogenesis [18]. Candida species must be able to effec-
tively colonize its host and likewise adapt to varieties of ex-
traneous constraints such as temperature, oxygen, pH, carbon
dioxide, and different negative biological conditions such as
carbon source, nutrient availability, the immunological sys-
tem, and other coexisting bacterial and fungal cells within
the niche [19, 20]. Positive response to those constraints has
an instantaneous effect in adaptation and promotion of
Candida virulence and pathogenicity.
Prior to receptor-mediated epithelial recognition by
Candida species, several signaling pathways are activated.
Temperature change, nutrient starvation, oxidative stress, os-
motic stress, and pH sensing trigger mitogen-activated protein
(MAP) kinase, cyclic Amp-based pathways, Rim 101 signal
transduction, and even genetic pathways that invariably
Eur J Clin Microbiol Infect Dis
induce many genes. Most of the induced genes are associated
with filamentous growth and biofilm formation. While diverse
genetic pathways transduce shifts from yeast to hyphae or
hyphae to yeast phase, different environmental signals posi-
tively and negatively modulate morphology-associated cell
surface switching [21]. The signaling and adaptation path-
ways play crucial roles in various physiological and cellular
processes involved in the pathogenesis of Candida species as
shown in Table 1.
Most of the signaling pathways are extremely essential for
shielding Candida spp. against immunological attack [40].
They play diverse roles in the expression of morphology-
associated genes. The co-expression of morphology-linked
proteins results in synergistic interaction among gene products
essential for biofilm establishment and growth within the host
[41]. Thus, for inhibiting Candida survival in host tissues,
interference with Candida species ability to integrate gene
expression to changes in morphology could be doubtlessly a
potential therapeutic strategy [42]. In addition, identifying sig-
naling components conserved among Candida species is cru-
cial for identifying potential drug targets.
During the process of pathogenesis, induced endocytosis
occurs. It usually takes place within 4 h of initial contact with
the cells of the epithelium. The induced endocytosis is a strat-
egy employed by Candida species to evade immune recogni-
tion. The recognition of invasins expressed on the fungal cell
surface triggers induced endocytosis. To date, only two invasins
(Als3p and Ssa1p) are known in C. albicans. The interaction of
the host epithelial cell receptors (E-cadherin) with invasins fa-
cilitates the remodeling of the actin cytoskeleton needed to
endocytose the organism. In a murine model of oropharyngeal
candidiasis reported by Sun et al., Als3 and Ssa1 mutants ex-
hibited reduced adhesion and invasion of epithelial cells [43].
Independent of the epithelial cell receptors, induced endocyto-
sis can also occur. This is possible via the interaction of the host
epithelial cell epidermal growth factor receptor (EGFR/HER2)
with the Candida cell Als3p and Ssa1p.
After induced endocytosis, the secreted virulence factors by
Candida species enhance their ability to penetrate the mucosal
surface. The oral and vaginal mucosa, which are terminally
differentiated and non-proliferative, are composed of stratified
layers less likely to facilitate invasion of fungi via induced
endocytosis. Candida species must utilize an alternative route
to invade a tissue less likely to support internalization in a
process called active penetration. Active penetration mediated
by means of hyphae extension (controlled by Ume6 and Eed1)
is a fungal-induced process that needs viable fungal hyphae
[44]. Physical forces, adhesion, and hydrolytic enzymes like
SAP also play a role. Candida albicans utilizes active penetra-
tion as the initial means to invade the outermost layers of the
epithelium in vivo. However, induced endocytosis could also
be evident of further enhanced invasion once the underlying
proliferative layers of the epithelium have been accessed by the
fungus. Thus, both active penetration and induced endocytosis
are mechanistically prominent strategies needed for infection
establishment through mucosal barriers in vivo.
In general, the pathogenesis of Candida starts with coloni-
zation, superficial infection, and deep-seated infection prior to
disseminated infection. The general steps in tissue invasion by
C. albicans include the following:
a. Adhesion to the epithelial cells
b. Colonization
c. Epithelial penetration/invasion by hyphae
d. Vascular dissemination
e. Endothelial colonization/penetration
Disseminated candidiasis only occurs when Candida es-
capes the immune system, penetrates vascular tissues, and
enters the blood. Entrance into the blood is via two routes:
a. Natural routes (via penetration of epithelial cells at muco-
sal cell surfaces)
b. Artificial routes (via implantation of medical devices, sur-
gery, and depletion of the natural microbiota by treatment
with antibiotics).
This second route is facilitated by biofilm formation as the
yeast cells can escape and enter the blood. It is important to
emphasize that the dispersal of the cells of the biofilm carries
clinical implications as the dispersed cells can instigate new bio-
film formation or spread into sensitive host tissue. For Candida to
survive and propagate in the blood, different genes are upregulat-
ed: genes involved in protein synthesis, glycolytic cycle, glycol-
ysis, and response to oxidative stress. The presence of Candida in
the blood leads to a condition called candidemia. From the blood,
the yeast is disseminated to various vital organs in the body where
it causes systemic infections. Disseminated candidiasis is highly
facilitated by extracellular hydrolytic enzymes, adhesins, pheno-
typic switching, and cytolytic proteins. Candida in the blood can
also give rise to candiduria as the organism can gain access to the
upper urinary tract (antegrade infection).
Although most infections involve biofilm formation, some
infections can occur without the formation of biofilm. In fact,
hyphae formation and growth are the starting points in the
pathogenicity of Candida species, except C. glabrata that
does not form hyphae. It is well known that several genes
directly or indirectly induced by environmental perturbations
trigger hyphae formation. The initiation and formation of hy-
phae are also affected by farnesol, a dominant quorum-sensing
molecule that acts via different pathways [45–47] (Table 3).
However, questions still remain regarding the mechanisms
controlling its synthesis, the receptors, and its transporter.
In summary, the switching of Candida spp. from commensal
to opportunistic pathogen is attributed to virulence factors
(discussed in subsequent sections) that are selectively expressed
 Eur J Clin Microbiol Infect Dis

Table 1 Major pathogenicity inducing pathways/responses in Candida species

S/ Pathways Functions Reference(s)

no.

1 Mitogen-activated protein kinase Important regulator of morphogenesis. [22, 23]

(MAPK) pathways
2 Ras-CAMP-PKA pathways
3 RIM 101 signal transduction
4 Stress response pathways
5 Ergosterol biosynthetic pathways
6 Genome plasticity
7 Calcium-calcineurin pathways
Involved in sensing and transmitting stress signals and other environmental signals
Three main MAP kinase pathways are the following: [24]
a. Mkc1- controls cellular integrity, invasive growth, cell wall biogenesis, and formation of
biofilm
b. Hog1- mediates response to thermal, osmotic, and oxidative stress. Controls cell wall for-
mation and morphogenesis. Under osmotic stress, its activation leads to glycerol accumu-
lation
c. Cek1- it mediates mating and hyphae formation and is also involved in adaptation to both
thermal and nutrient stresses.
Regulate adhesion, dimorphism. Also involved in the formation of biofilms. [23, 25, 26]
Control hyphal formation and white-to-opaque change [27, 28]
Involved in drug tolerance and in the maintenance of cell wall integrity
Enables Candida albicans to sense pH changes, thus mediate pH-dependent responses [29]
Contribute to virulence and pathogenesis [30]
Facilitate adaptation to ever-changing environmental conditions
Protect against host-derived stresses
Link between hyphae formation and virulence in C. albicans [31]
Enhance cell adhesion and damage to the tissues [32]
ERG3 and ERG11 play major roles in azole drug resistance; thus, it is the target of fluconazole
antifungals
Triggers adaptation to fluctuating host environment
Leads to the generation of recombinant progeny with increased fitness
Induces natural mutations that alter the balance between commensalism and pathogenicity. [33, 34]
Facilitates resistance to stressors including antifungal agents and pathogenicity during systemic [35]
and mucosal infections
Triggers polarized filamentous growth
Involved in the generation/evolution of new pathotypes or strains
Enhances the utilization of several nutrients
Facilitates Candida growth rate, as well as its morphology and behaviors at the host interface
Major mediator of stress responses [36]
Essential for survival in the presence of stressors [37]
Play crucial roles in virulence [38, 39]

under suitable predisposing conditions. Most of these virulence
factors are under tight regulation. More studies in their regula-
tory mechanisms could be very vital in the quest for new anti-
fungal agents. Figure 1 is the major network of Candida viru-
lence and pathogenesis showing the connections between the
various pathogenic determinants and virulent factors.
Host response to Candida species
The host epithelium is often in constant interaction with Candida
species and the transition from commensalism to infection usually
leads to various modifications in the interplay between the fungus
and the host [58, 75]. The cells of the epithelium can differentiate
between pathogenic and non-pathogenic Candida species in re-
sponse to which they induce specific signaling pathways [76] as
stated in the previous section. The pathogen recognition receptors
(PRRs) in the host recognize fungal carbohydrates and other
pathogen-associated molecular patterns (PAMPs) in the fungal
cell wall. This recognition facilitates the activation of the immune
cells and subsequent production of cytokines [77].
Thus, the invasion of the cell into the tissue triggers the release
of danger-associated molecules such as interleukin-1α (IL-1α)
and chemokines. Both IL-1α and chemokines promote the re-
cruitment of immune cells, such as neutrophils and monocytes to
the site of infection [78] where they abruptly contribute to the
defense against the fungi [79]. It is important to note that host
defense against systemic candidiasis is dominated by the activity
of neutrophils and monocytes which repress fungal proliferation
and dissemination [80]. During vulvovaginal candidiasis, neutro-
phils may also promote the development of disease symptoms
[81]. It is becoming evident that the host response to Candida
adhesion/invasion varies in a strain-dependent manner as the bal-
ance between commensalism and pathogenicity is determined by
Eur J Clin Microbiol Infect Dis

Environmental constraints Signaling/adaptation pathways

Stress Genome
response
plasticity Metabolic
Hsp 90, Hsp 60, flexibility
Hsp 70, Hsp 21,
Hsp 12, Hsp 104

Fungal PAMPs are hidden from the

Antifungal
immune system or not produced by drug resistance
Proteinase (SAP),
Site of colonization

the yeast forms during colonization EFG1, ECE1, HWP1, INT1, Cytolytic proteins
phospholipase, lipase,
Morphology Extracellular
ENO1, TEC1, ALS3, BCR1, (Candidalysins)
Oro-pharyngeal associated/Virulent hydrolytic enzymes hemolysins, coagulase,
Lower + upper digestive tract HYR1, NRG1, UME6, FLO8,
encoding genes esterases, etc.
Genital tract CZF1, EED1, CPH1, TUP1,
Urinary tract etc.
bloodstream Superficial

Candidiasis
infection
Induced
endocytosis
Thigmotropism
Epithelial Endothelial Deep seated
Tissue infection
adhesion/invasion adhesion/active
Cln1, Pes1, Eed1, Ume6 penetration
Planktonic TUP1, NRG1 Hyphae formation Active
Yeast cells Adherence to
Candida cells and extension penetration Systemic infection
overgrowth cells surfaces
Predisposing factors

Tissue invasion & (septicemia)

Long period of hospitalization penetration
Use of antifungal agents
Overuse of antibiotics Danger associated
Use of invasive devices
Blood vessels molecules (DAM)
Use of immunosuppressive agents Biofilm formation Cytokines
Surgical procedures
(Candidaemia)
and dissemination (Interleukin (IL- IL-17))
Diabetes, AIDS, old age, cystic fibrosis
Chemokine
Organ transplants
NLRP3 inflammasome

Farnesol Phenotypic Increased Host Recruitment of

Evasion from host
(Quorum sensing molecule) switching virulence microbiota
immune system immune cells

Fig. 1 Simplified diagram illustrating the network of Candida virulence types of candidiasis (8). Yeast cells can enter the blood (7) and then
and pathogenicity. (1) Planktonic yeast cells attach to surfaces. Favorable disseminate to the vital organs where they establish new biofilms.
conditions facilitate overgrowth; adherence (2): the cells attach to host Infections associated with biofilms are of great clinical significance.
cells via adhesins; hyphae formation/extension (3): environmental con- Major Candida infections include vulvovaginal, oropharyngeal, and gas-
strains induce the HSPs, signaling and adaptation pathways which induce trointestinal candidiasis, candidemia, candiduria, and intra-abdominal
morphology-associated genes. The formation of the hyphae marks the candidiasis. Key: dashed lines: signals and inductions; single-headed
beginning of Candida pathogenesis. Epithelial/endothelial adhesion/inva- thick dark red arrow: major route of Candida pathogenesis; curved
sion (4 and 6): this is facilitated by hydrolytic enzymes and it is achieved double-arrow connector: interaction/association between factors; T-
via two ways: induced endocytosis and active penetration. Some species shaped thin red line: inhibitory signal. The pool of virulence encoding
such as C. glabrata do not form hyphae; rather, they form biofilms (5) genes house both the genes involved in hyphae and biofilm formation and
prior to the establishment of infection. Destruction of epithelial and mu- other vital processes crucial for pathogenesis
cosal surfaces by the enzymes and cytolytic proteins gives rise to different

distinct host responses triggered by intraspecific diversity of the the fact that mutants lacking in filamentous growth are less
Candida species [34]. Irrespective of the nature of the strain virulent [82]. In fact, hyphal growth and biofilm formation are
infecting the host, IL-17 signaling plays a nonredundant part mainly the core factors that enhance the progression of path-
for mucosal immunity against Candida. On the other hand, ogenicity in Candida spp. [83]. Candida albicans, the major
strain-specific dichotomy is displayed by epithelial cell damage, species implicated in candidiasis, has the ability to regulate its
inflammation of the mucosal and neutrophil infiltration, all of switch to filamentous form. Over the years, hyphae formation
which are associated with fungal pathogenicity [34]. Therefore, and its transition to yeast form or vice versa have attracted
diverse immunological pathways differ in their roles in antifungal tremendous attention to scientists. The ease with which hy-
immunity. The selective induction of distinct immune mechanism phae penetrate the mucous membrane, invade the tissues, and
results from variation in the fungus and this activation influences gain access to the bloodstream is very important in the estab-
the outcome of the microbe-host interaction. lishment of candidiasis, most especially candidemia [84].
Candida albicans, C. tropicalis, C. dubliniensis, and more
recently C. auris have all been reported to form hyphae [13],
Determinants of pathogenesis/virulent although under restricted range of conditions. However, most
factors of the other Candida species such as C. glabrata only form
pseudohyphae and yeast. Incubation in serum, alkaline, or
Hyphae formation mediated neutral pH, low concentration of oxygen, increased CO2, cell
by morphology-associated genes/transcription density via quorum-sensing molecules, carbon, and nitrogen
factors starvation are some of the environmental stimuli that facilitate
yeast to hyphal switching [85]. The inputs of various internal
Proliferation of hyphal forms of Candida gives its invasive and external environmental stimuli are integrated by the fun-
and penetrative ability into host tissues. This is justified by gus to ascertain if hyphal morphogenesis is to be initiated.

Interestingly, when there is no external stimulus, hyphal mor-
phogenesis can also be induced [13].
Till date, the exact mechanisms that facilitate C. albicans
transition from yeast form to hyphae form are yet to be
completely elucidated. However, several transcription factors
(TFs) have been shown to influence hyphae growth [86].
Some of the identified TFs include Tup1, Ngr1, Rim101,
Cph2, Cph1, Czf1, Efg1, Tec1, Flo8, Ume6, Fkh2, and
Mcm1 (Table 2). The major transcription factor genes required
for hyphal invasion according to Desai and co-workers in-
clude ERG1, TEC1, NDT80, ROB1, DPB4, and EFG1 [19].
Under favorable conditions, most of the TFs (except Ume6)
are essential for hyphal growth but their expression is not
always enough to modulate real hyphal morphogenesis. TF
mutants are defective in hyphal morphogenesis and biofilm
formation. They also exhibit reduced filamentation and are
defective in invasive growth except the Nrg1 and Tup1 mu-
tants which exhibit enhanced filamentous growth [114, 115].
A reduced Efg1 gene expression suppresses true hyphae for-
mation [97, 98, 108]; however, Tec1 overexpression restores
filamentous growth in an Efg1 mutant. The activation and
repression of genes associated with hyphae formation are reg-
ulated by Efg1p and Nrg1p. Koch et al. reported that limiting
the endogenous nitric oxide (NO) levels stabilizes the tran-
scriptional repressor, Nrg1 and inhibited the yeast-to-hyphal
transition [116].
In the early 2000, the relationship between hyphae-specific
gene expression and morphology and its link to pathogenicity
was a process that was not fully understood. In trying to un-
ravel this, HWP1 and ALS3, two genes that are highly upreg-
ulated during filamentous growth, were discovered by early
researchers [44, 87]. The activation and repression in HWP1
involve HWP1 control region (HCR). It is yet to be complete-
ly understood how these processes are associated with the
genetic programs controlling morphogenesis. However, ac-
cording to Kim et al., the morphology-associated mRNA iso-
forms occur during yeast and hyphal growth in Candida
albicans. These isoforms are very vital for coupling the ex-
pression of gene to morphology [41]. Other researchers have
also reported several genes and proteins directly or indirectly
linked to morphogenesis and general Candida virulence [117,
118]. However, Reyna-Beltran and Iranzo in a recent study
reported that ENO1 (Table 2) found in Candida albicans
could be a potential target for designing new drug against
candidiasis due to its important role in virulence [102, 103].
Generally, hyphae formation among pathogenic fungi cre-
ates a suitable environment for movement within the sur-
rounding niche, mediates adherence, facilitates acquisition of
nutrients, interferes with other essential biome functions, and
enhances virulent fungal growth. Hyphal formation is as im-
portant as its elongation and branching. However, the elonga-
tion of hyphae can be controlled by endocytosis modulation.
Alterations in many cellular functions (e.g., endocytic
Eur J Clin Microbiol Infect Dis
pathways) as recently reported by Bar-Yosef et al. [119], in
addition to many signaling pathways, are required for effec-
tive hyphal development. Not much is known about hyphal
elongation and branching. Less attention has also been given
to the yeast promoting regulators (hyphal repressors). More
attention should be focused on this area. In addition, re-
searchers should make more efforts to identify more genes
that are usually upregulated during morphological transition
in Candida species. This is because effective drugs can be
developed by targeting those genes. Generally, any substance
that can inhibit the activities of such genes and the transcrip-
tion factors can reduce pathogenicity [120]. Furthermore, the
transcription factors (TFs) activated by several signaling path-
ways [121] are enriched in pathogenic Candida species. They
are crucial for cell functions and response in diverse niches. In
Candida species, they encode and coordinate essential cellular
functions such as hyphal morphogenesis (yeast to hyphae for-
mation), biofilm formation, and drug resistance, in addition to
pathogen to commensal transition [122]. More should be
learned on how they perform these roles and to discover
new TFs.
Finally, in non-albicans Candida species, the exact role of
hyphae formation as well as most of the virulence genes is still
not clearly understood. However, Banerjee et al. in his study
showed that hyphae formation leads to decreased virulence
and pathogenesis in C. parapsilosis and C. tropicalis [123].
According to the study, non-albicans Candida should be stud-
ied separately to comprehensively gain further insight on the
main function and reasons for filamentation. This current ob-
servation makes it clear that other virulence attributes besides
hyphae formation can play vital roles in most of the non-
albicans Candida species. Despite this, more studies on hy-
phae formation in both albicans and non-albicans Candida
species are warranted.
Phenotypic switching
Candida spp. are able to survive, thrive, and establish infec-
tion in the host due to its ability to undergo reversible change
between different sets of morphologies. The diverse morpho-
logical phenotypes are critical for adaptation in ever-
fluctuating environmental conditions. How pathogenic
Candida spp. are able to adapt, survive, and propagate in
diverse host environment can be answered by understanding
the mechanisms controlling phenotypic switching system.
However, questions as to why C. albicans integrate morpho-
logical switch as part of its sexual life cycle are still not clearly
understood. To achieve mating competency, MTL homozy-
gous Candida spp. must switch to opaque cell from normal
yeast cell morphology [124]. This process is highly facilitated
by several signals [125]. The phenotypic switch turns on as
soon as the signals are dominated, leading to the establishment
of superficial infections (skin and mucosa) as well as invasive
Eur J Clin Microbiol Infect Dis

Table 2 Morphology/hyphae-associated genes and their functions

S/ Genes Name Functions References

no.

1 HWP1 Hyphal wall protein Involved in hyphae growth and adhesion in C. albicans [87, 88]
Important in biofilm formation [89]
2 ALS3 Agglutinin-like sequence protein Encodes glycosylphosphatidylinositol (GPI)-associated cell surface glycoproteins [44]
Encodes Als3, member of Hsp90 [60, 90, 91]
Involved in hyphae growth and adhesion in C. albicans [15]
Acts as an invasin and mediates induced endocytosis
Plays a role in biofilm formation
3 HYR1 Hyphal-regulated protein Mediates filamentation and growth [92]
4 ECE1 Extent of cell elongation protein Hyphal-specific gene expressed during filamentous growth in C. albicans. [93]
Encodes candidalysin, a pore-forming toxin, mediates mucosal epithelium damage [58]
during invasion.
The peptide 3 causes cell death by making a hole on host cell membrane
5 TEC1 Transcription activator Its overexpression restores filamentous growth in Efg1 mutants
Regulates hyphae development and cell adhesion genes [94]
Controls the formation of biofilms [95]
Regulates gene expression during internal colonization and
Required for SAP expression. [96]
6 EFG1 Enhanced filamentous growth Located downstream of cAMP-PKA signaling, it governs morphogenesis [41]
(yeast-to-hyphae transition)
Encodes a transcription factor, Efg1p, an important regulator of HWP1 and ALS3 [97, 98]
Involved in stress tolerance, modulation of genes necessary for metabolism,
phenotypic switching and cell elongation, biofilm formation and pseudo hyphal
filamentation.
7 INT1 Integrin-like sequence Involved in hyphal formation and adherence [99]
8 BCR1 Biofilm and cell wall regulator 1 Regulate the expression of genes that control cell surface properties
Serve as link between gene expression and hyphal differentiation. [100]
Major control of biofilm formation [101]
9 ENO1 Enolase 1 Encodes a transglutaminase (TGase) needed in cell division, growth, [102, 103]
yeast-to-hyphae transition and protection against osmotic stressors.
Involved in posttranslational modification
Enhances invasion
10 EED1 Epithelial escape and dissemination Required for initiation and sustenance of filamentation [104]
Mediate dissemination within epithelial tissue
11 UME6 Transcriptional regulatory protein Important for proper expression of hyphae-specific genes [105]
Important for hyphae elongation
Required for adherence to surfaces [106]
Promote filamentous biofilms [107]
12 ACE2 Controls hyphal morphogenesis [108]
13 Others CPH1, CZF1, FLO8, EED1, BRG1 Positive regulators of filamentous growth [109, 110]
TUP1, NGR1, RFG1 Negative regulators of filamentation (repress hyphae-specific genes) [111–113]

bloodstream infections, especially in individuals with dilapi-
dated immune system [126]. Soll et al. [127] observed that due
to reduced surface expression of invasins and inability to in-
duce the receptors of epidermal growth factor, opaque cells
(just like white cells) showed reduced invasive ability and
decreased ability to damage epithelial cells. White-gray-
opaque phenotype discovered in C. albicans is also another
morphological switching system [128]. This phenotypic
switching system in C. albicans was known to facilitate fit-
ness, offer adaptive advantage, and play several biological
roles in cells that possess them. Generally, phenotypic
switching is regulated by WOR1 which encode a transcription
factor. The default phenotype is the white phase. Czf1, Efg1,
Wor2, Wor1, Ahr1, and Wor3 are the transcription factors that
regulate WOR1. According to Tao et al. [127], two transcrip-
tion factors (Wor1 and Efg1) regulate white-gray-opaque

transition [128]. WOR1 is mainly expressed when cells are in
the opaque state. Thus, Wor1 is necessary for opaque cell
formation. In other to understand how Wor1 induces and sus-
tains opaque state, Alkafeef et al. showed that the mode of
action of Wor1 is via repression of Tup1 activity [129]. This
Tup1 (overall transcriptional repressor) is the major inhibitor
of the opaque phenotypic state. This observation explains the
mechanism used by Candida to change from a commensal to
an opportunistic pathogen.
The involvement of Efg1 in the regulation of phenotypic
switching demonstrates the multiple roles of Efg1 gene in the
pathogenicity of Candida spp. In addition, both Sac7 and
Rho1 also control switching system in Candida albicans
[130]. It is safe to assume that certain environmental cues
and even some specific genetic configurations (mating type
locus) greatly influence the increasing regulatory networks of
phenotypic switching. Studies have shown that opaque phe-
notypes are less virulent than the white phenotypes. This is
because the opaque cell lacks the ability to produce chemo-
attractants for polymorpho-nuclear cells (PMN) [61]. The
transition generally facilitates mating and host colonization.
Phenotypic switching greatly influences virulence and
pathogenesis. It enables C. albicans to avoid recognition by
cells of the immune system depending on the environment
[131]. In a recent study by Perini et al., white-opaque
switching in C. tropicalis was found to change host-
pathogen interactions in an infection model [132]. However,
the details of how it influences commensalism and pathogen-
esis in humans still remain speculative. More studies are need-
ed to completely clarify and understand whether the pheno-
typic switching, in addition to the phenotypic developmental
and regulatory states, is actually a valid representation of
events in the human host. Understanding the control/
regulatory process of phenotypic switching could be vital in
answering the questions as to why pathogenic Candida spe-
cies adapt and survive in diverse unfavorable environment.
Biofilm formation
Biofilm is one of the major virulence attributes of Candida
spp. Biofilm formation is involved in majority of Candida-
associated infections. During biofilm formation, cells adhere
to both biotic and abiotic surfaces. The cells, thereafter, are
embedded in extracellular matrix [95]. The extracellular ma-
trix acts as a protective material for various Candida spp. This
virulence property enhances adhesion, hyphae formation, and
penetration of the yeast cells. Candida biofilm formation en-
hances its colonization ability. It also protects the cell against
immunological attack (especially against neutrophils) and pre-
vents ROS formation that is extremely detrimental to the or-
ganism [133]. Due to the ability of the cells encapsulated in
the extracellular matrix to resist immunological attack, resist
antifungal drugs, and facilitate persistence, biofilm formation
Eur J Clin Microbiol Infect Dis
carries great clinical implication [134, 135]. Candida biofilms
also induce efflux pump transporters [136]. The reduced sus-
ceptibility to antimicrobials during biofilm formation is due
to:
1. Inability of the drug to pass through the extracellular poly-
saccharide matrix of the biofilm
2. Antagonism of the drug caused by accumulation of waste
products and nutrient depletion
3. Physiological alteration of the fungi
In surfaces like catheters, dentures, and other implants,
C. albicans has a remarkable biofilm-forming ability. The for-
mation of biofilm on devices negatively affects the host via
device failure and by acting as a source for future continued
infections [137]. Generally, the mortality rate of fungal infec-
tions associated with medical devices is high (up to 30%)
[138]. Biofilm formation is more commonly associated with
C. albicans. However, recent studies have shown a high rate
of biofilm-forming ability among non-albicans Candida spp.
[139] Candida glabrata, C. tropicalis, C. parapsilosis, and
C. auris can all form biofilm [140]. Proteins such as secretory
IgA, lysozyme, mucin, and lactoferrins have inhibitory effects
on Candida that stop adhesion and multiplication on the mu-
cosal surface [141, 142]. The Candida hyphae and extra poly-
meric materials increase biofilm growth and structural integ-
rity [141, 143].
Biofilm formation generally involves sequential processes
as shown in Fig. 2. Several genes are differentially upregulat-
ed during the process. There is upregulation of adhesion genes
involved in attachment. On the other hand, there is downreg-
ulation of genes coding for adhesins, influencing yeast cell
dispersal [144]. Als3 plays the most important role [88].
However, EPA (epithelial adhesion) is the main adhesin re-
sponsible for biofilm formation in C. glabrata [145]. The
expression of adhesins during biofilm formation is under the
control of TFs which also control filamentation [146]. Genes
that are also involved in hyphae formation also play crucial
roles during biofilm formation (Table 2). The key resistance
determinants for various Candida species involve the forma-
tion of extracellular matrix (ECM). The ECM induction and
production, however, are highly regulated processes involving
several genes and TFs. It is important to emphasize that a
transcriptional network that is highly complex and associated
with morphogenetic switching controls biofilm formation in
Candida spp. [144, 147] It has been shown that the biofilm TF
network is highly sensitive to genetic constrains [96].
Moreover, environmental perturbance that affects the gene
has an influence on the TFs associated with biofilm formation.
In summary, the overall regulatory network needed for bio-
film formation is a complex process requiring the regulation
of adhesins, formation of hyphae (morphological modifica-
tion), production of extracellular matrix, and the regulation
Eur J Clin Microbiol Infect Dis

Fig. 2 Biofilm formation cycle in Planktonic yeast Bcr1, Als3, Als1, Ece1, Hwp1, Hwp2,
Candida species. Yeast cells 1 cells Eap1, Rbt1, Ywp1, Pga10, Csh1, Pbr1
attach to substrate and to other 3
cells via the adhesins. The cells
proliferate to form microcolonies. Proliferation
This is followed by germ tube, Biotic (host cell)
Abiotic (indwelling
pseudohyphae, and hyphae medical devices)
formation. Some Candida species Morphological
Microbial cells Yeast cells adhesion
do not form hyphae. During modification
maturation, there is expansion of
2
biofilm biomass, as well as the
formation and accumulation of
extracellular matrix (ECM). Better adherence and
Finally, the yeast cells disperse enhanced biofilm
formation
and initiate the formation of new
Biofilm formation cycle
biofilms. Biofilm formation is
inCandida species
controlled by several genes,
including hyphae-associated
genes. Most genes are involved in
more than one role. Several TFs
4
also regulate the process. The
major TFs in C. albicans include Formation of hyphae
Ndt80, Rob1, Gal4, Rfx2, Flo8, Dispersal of yeast cells cells and mycelium
Efg1, Brg1, Tec1, and BCr1 6 Ngr1, Ume6, Pes1
Hwp1, Ece1, Epa 6, Efg1,
Tec1, Bcr1, Eed1, Flo8,
Czf1, Spt20, etc.

5
Maturation (formation of
7 extracellular matrix)
1. Antifungal resistance
Adh5, Zap1, Fks1, Gca1, Gcn4,
2. Increased virulence and pathogenicity
3. Facilitating sharing and transferring of genetic Rlm1, Gca2,Csh1, Flo8,
materials, Ndt80, Brg1, Rob1, Rbt1 etc.
4. Trigger physiological changes
5. Facilitate communication via signaling
molecules
6. Enhance development of higher adhesion
forces
7. Increase in resistance to diverse stresses

of other vital cellular processes [145]. The fact still remains
that there is a complexity of mechanisms that are involved in
biofilm formation. These mechanisms are often times specie
or strain specific. Several factors, both internal and external,
including the presence of antagonistic or synergistic bacteria
and fungi have a significant effect on the final features of the
formed biofilm. One of the very tasking goals is identifying a
central regulator to tackle the regulatory control of biofilm
formation in all Candida spp. Further studies on the various
mechanisms that facilitate biofilm formation and their regula-
tion in both C. albicans and non-albicans Candida species
will help greatly in developing more effective ways to tackle
Candida infections. Lagree et al. reported that surface topog-
raphy may impact biofilm formation by C. albicans [148],
which means that the use of topographic coatings may likely
be a viable approach in the control of C. albicans. Most stud-
ies on Candida biofilm formation have been based on in vitro
models, making it more difficult to translate these findings
into real infection in humans [149]. In vitro biofilm models
that take into consideration in vivo conditions should be de-
veloped. Substances that could bind to and inactivate the
major biofilm regulators could be vital in preventing
biofilm-associated Candida infection.
Metabolic flexibility/nutritional factors
The metabolic capacity to assimilate host nutrients (carbon) is
a fundamental prerequisite in the survival and establishment
of Candida infection and must be regulated. Metabolic flexi-
bility is an important virulence factor that offers adaptive ad-
vantages to Candida spp. Competition with the host microbi-
ota for available nutrients is one of the routine behaviors as-
sociated with Candida albicans in the gastrointestinal tract.
During infection, depending on the anatomical site, several
nutrient sources are used by Candida spp. Glucose, proteins,
amino acids, and lipids derived from the host are nutrients
used by C. albicans and other species [150].
Generally, Candida utilizes different pathways in the me-
tabolism of its nutrients. Disruption in any of the steps in-
volved in the pathway reduces colonization and virulence.
During infection, different carbon sources (sugar and non-
sugar) are used. The ability of Candida spp. to effectively

utilize GLCNAC stimulates and modulates pH and hyphal
growth. Metabolic flexibility, therefore, confers an edge for
virulence [151]. It has been reported that growth in carboxylic
acids and lactate result in profound changes to the C. albicans
cell wall, by masking β-glucans, an effective immune evasion
tactic [152]. The presence of these nutrients results in a change
in cell wall components of C. albicans [152]. The β-glucan,
an important cell wall component, is usually concealed during
the process. The covering of β-glucan is an effective mecha-
nism for evading the host immune system.
During invasive infections, gluconeogenesis, glyoxylate
cycle, and β-oxidation of fatty acids are usually upregulated.
Most importantly, the glyoxylate pathway, a vital metabolic
pathway seen in Candida spp., is essential for survival during
nutrient starvation and other adverse environmental condi-
tions. For patients undergoing antibiotic therapies,
C. albicans can outgrow the other organisms. In the blood
stream, there is high abundance of glucose for use by
C. albicans. However, C. albicans faces nutrient starvation
when phagocytosed by immune cells. When C. albicans is
completely covered by the macrophages, the organism not
only switches from glycolysis to gluconeogenesis but also
switches to glyoxylate cycle. This switching is fully aided
by isocitrate lyase and malate synthase, the two important
enzymes of the glyoxylate cycle. This switch in the pathway
enables C. albicans to thrive inside phagocytic cells (e.g.,
macrophages and neutrophils) which are completely lacking
in nutrient [153]. The glyoxylate cycle is not only essential for
Candida survival when engulfed by macrophages and neutro-
phils but also essential for virulence [154]. The two key en-
zymes (isocitrate lyase and malate synthase) are potential at-
tractive targets for the development of new drugs [155].
During the development of resistance to antifungal agents
(such as the azoles), metabolic pathways are usually altered
with significant change in the cell wall contents of
C. albicans [156]. Recently, Laurian et al. explored the
uninvestigated aspects of glycolytic metabolism in Candida
and showed that the two enzymes, hexokinase and glucoki-
nases, are important for morphology transition, cell fitness
and mediate virulence, and pathogenicity [157]. In addition,
Han et al. reported two key enzymes, NAD+-dependent gluta-
mate dehydrogenase (GDH2) and NADPH-dependent gluta-
mate dehydrogenase (GDH3) [158] that are involved in main-
taining redox balance in C. albicans cells. They play an impor-
tant role in the morphogenesis of C. albicans and could be
potential targets for blocking the morphological switching in
C. albicans. Thus, the understanding of the genes involved in
cell redox balance could help to better understand C. albicans
morphogenesis [158].
Nutrient accumulation triggers the expression of diverse
genes needed for its uptake and utilization. During the inva-
sion and damage by Candida species, iron-related genes are
usually expressed. Iron is an essential component required for
Eur J Clin Microbiol Infect Dis
Candida virulence. In the pathogenicity process of
C. albicans, hyphae formation is activated during invasion
while the iron scavenging process is activated during the dam-
age phase. In a review, Fourie et al. stated that the presence of
iron had a great influence in the ability of C. albicans to switch
from a commensal to a pathogen [159]. Iron also has a great
influence on disease outcomes.
In summary, host-pathogen interactions are greatly affected
by nutrient metabolism and flexibility. Several nutrient
sources exert great influence on fungal fitness, act as signals
that influence resistance to multiple stresses, and even affect
the cell wall structures. Candida glabrata also utilizes viable
alternative carbon sources required to persist in the host [160].
The ability of Candida spp. to respond to changes in nutrient
availability, induced by the host, is very important in its path-
ogenicity [150]. It has become evident that fungal nutritional
acquisition systems, transport, and competition (scavenging)
are all involved in the regulation of Candida virulence. This
underlying regulatory scheme may provide the basis for the
development of potential therapeutic targets in the future.
Therefore, given that metabolites can act as future biomarkers
for drug development, an understanding of the pathways of
central metabolism in Candida, especially among the non-
albicans species, could help in suppressing these fungal
pathogens.
Synergistic coaggregation with resident microbiota
The complex community of microbes interact among them-
selves and this interaction has co-evolved to maintain relative
homeostasis [161, 162]. Different human bacterial microbiota
highly coexists with Candida species [163]. However, fungi
are a small part of the microbiota when compared with bacte-
ria [164]. Bacteria have the ability to support or interfere with
the nearby fungal cells and vice versa [165]. The association
and interactions between microbes are necessary for the main-
tenance of a healthy microbiota. It is one of the most notewor-
thy areas of intense research since the beginning of the twen-
tieth century [166]. Alterations in the interactions between
microbes lead to the overgrowth of Candida species. This
often carries significant negative effect on human health espe-
cially in immunocompromised individuals [167].
Intense interactions between bacteria and C. albicans have
direct implication in the pathogenesis and treatment of infec-
tions caused by the fungus. Candida blood stream infections
are often accompanied by about 25% of bacterial infection.
The two major bacteria most commonly isolated from infec-
tions with C. albicans include Staphylococcus (mostly aureus
and epidermidis) and Pseudomonas aeruginosa. Synergistic
colonization of the host or indwelling medical devices by
these pathogens result in mixed biofilm formation. This is
often associated with increased virulence and pathogenesis,
in addition to increased resistance to antimicrobial agents
Eur J Clin Microbiol Infect Dis
[163, 168]. The coaggregation of two microbial species
(C. albicans and Streptococcus mutants) in biofilm formation
often results in biofilms with higher biomass, as well as mu-
tual benefits than the biofilm formed by a single species [169].
Candida albicans can also form synergistic interaction with
other Candida species like C. glabrata [170]. This interaction
under diverse environmental conditions can greatly influence
hyphae formation, phenotypic switching, biofilm formation,
resistance to antifungal drugs, and virulence. The binding be-
tween hyphae of C. albicans and C. glabrata facilitates the
proliferation of C. glabrata in oropharyngeal candidiasis
[171]. During invasion of mucosal barriers, Staphylococcus
aureus attaches to the hyphae formed by C. albicans. The
biofilm formed by S. aureus results in increased Candida vir-
ulence. It also provides the bacteria with protection against
host immune cells and antimicrobial agents [168]. It is, there-
fore, evident that mutually beneficial biofilms can be formed
by C. albicans and other commensal bacteria and fungi.
However, it is also important to emphasize that not all
bacteria-Candida associations are beneficial. The colonization
with specific bacteria species can reduce Candida load and
pathogenesis. In a recent study, E. coli not only outcompetes
C. albicans but also produces a substance that kills Candida
cells through a magnesium-dependent mechanism [172].
Camarillo-Marquez et al. demonstrated the antagonistic inter-
action of Staphylococcus aureus towards C. glabrata [173].
The data showed that S. aureus repressed the proliferation of
C. glabrata and caused cell death via an apoptotic mechanism.
Bacteria-induced suppression of filamentation can be alleviat-
ed by the depletion of bacteria by antibiotics thereby facilitat-
ing the shift of Candida from a commensal to pathogenic state
[174]. Additionally, the interaction between Candida species
can affect biofilm formation, formation of hyphae and gene
expression crucial for virulence and establishment of infec-
tion. As reported by de Barros et al., C. tropicalis antagonis-
tically affects C. albicans biofilm formation, yeast-to-hyphae
transition in addition to altering its virulence attributes [175].
Finally, most studies on synergistic coaggregation have been
focused on C. albicans. There is need to pay attention to non-
albicans Candida interaction with oral bacteria.
Understanding the molecular interplay between bacteria,
Candida and the host is very important since such interactions
greatly determine disease outcomes.
Extracellular hydrolytic enzymes and proteins
Hemolysins
The ease with which pathogenic microorganisms acquire iron
is essential for their adaptation and survival. Most pathogenic
organisms obtain iron from hemoglobin. Hemoglobin is a
common compound containing iron as there are no free iron
molecules in the host [176]. However, to do so, the organism
must have a mechanism that enables it to damage the hemo-
globin and release the iron. This mechanism involves the pro-
duction of the lytic protein called hemolysins [176, 177].
Thus, the remarkable ability of hemolysins to facilitate path-
ogen survival and persistence due to the acquisition of iron,
hyphal invasion in cases of systemic candidiasis, or dissemi-
nated candidiasis makes it a very important virulence factor
[55, 56, 178].
As previously reported by Luo et al., hemolysins are
grouped in three categories: beta (complete), alpha (incom-
plete), and gamma (non-hemolytic) [179]. Candida albicans
and non-albicans Candida species are beta hemolytic
[180–182]. Yigit and Aktas showed that Sabouraud dextrose
agar supplemented with sheep blood was the best and most
sensitive medium to demonstrate hemolysis by Candida spe-
cies [183]. High rate (94.8%) of hemolysin production by
Candida albicans was reported by Sachin et al. [184]
However, most non-albicans Candida species also demon-
strated similar ability to produce hemolysin when compared
with C. albicans, thus, suggesting the pathogenic capacity of
the emerging non-albicans Candida species [55]. Blood glu-
cose concentration, presence of electrolytes, and strain geno-
type of Candida species are some of the factors that influence
hemolysin production. In Candida species, the three electro-
lytes, CaCl2, NaCl, and KCl, can cause decrease in hemolysin
production [185]. A rise in blood glucose level may positively
influence hemolysin production [176]. In a contrary observa-
tion, Arslan et al. showed that diabetes and caries do not have
any influence on Candida virulence [186]. However, unlike
other enzymes, the exact role of hemolysins in fungal infec-
tion is not well understood [185].
Phospholipases
Phospholipases are ubiquitous group of hydrolases that cata-
lyze the breakdown of phospholipids into fatty acids and other
lipophilic substances. They are very important heterogeneous
group of hydrolytic enzymes that cleaves the ester bonds of
phospholipids resulting in host cell penetration and cell lysis
by organisms [52, 187]. Due to its vast role in systemic infec-
tion, the production of phospholipases can be seen as one of
the major criteria to distinguish virulent invasive strains from
noninvasive strains in Candida species.
In a study by Tsang et al., phospholipase production was
observed in 30–100% of Candida isolates [56] while Jasim
et al. reported phospholipase production in 40 (80%) out of 50
Candida spp. [182] There are four phospholipases (phospho-
lipase A, B, C, D) [188]. Phospholipase B1 and B2 products
have been observed extracellularly. Both B1 and B2 are
known to take part in the destruction of the host cell [189].
In C. albicans, seven genes coding for phospholipase have
been implicated: PLA, PLB1, PLB2, PLC1, PLC2, PLC3,
and PLD1 [190]. Most of these genes have been characterized

but a lot still remain to be learned with reference to their role in
virulence most especially among the non-albicans Candida
species. Candida albicans is usually the most potent phospho-
lipase producer. The low phospholipase activity in majority of
the non-albicans Candida species suggests that the enzyme is
probably not a significant virulence attribute for these species.
Non-albicans Candida spp. such as C. glabrata, C. tropicalis,
C. krusei, and even C. parapsilosis have been reported to
produce phospholipase [191]. Thus, more attention should
be focused on studying the phospholipase potentials of non-
albicans Candida spp. since this enzyme correlates with anti-
fungal resistance and plays an important role in increased
disseminated of infection.
Proteinases
Proteinase is an important enzyme that cleaves or breaks down
vital proteins [51]. There are four categories of proteinase:
serine proteinase, aspartyl proteinase, cysteine proteinase,
and metalloproteinase. Candida secretes secretory aspartyl
proteinases (SAP). SAP is one of the multifunctional mole-
cules involved in Candida pathogenesis. SAP production by
fungi increases colonization and penetration of the host tissue.
The expression of different SAP genes correlates with disease
types; hence, SAP is one of the major determinants for differ-
ent types of candidiasis [50, 51] (Table 3). SAP genes ranging
from SAP1–SAP10 have been identified in C. albicans [190,
192]. While Aya et al. [193] and Lima et al. [194] reported the
distribution and high frequency of SAP genes and antifungal
genes in Candida isolates recovered from vulvovaginal can-
didiasis, Kadry et al. [49] showed a link between the forma-
tion of biofilm and SAP prevalence in resistant Candida
albicans isolates. Ramos et al. [195] reported that all isolates
of C. albicans and majority of the non-albicans isolated from
cases of cutaneous candidiasis produce SAP. Both albicans
and non-albicans species produce and spontaneously express
SAP genes. Candida glabrata, C. tropicalis, C. parapsilosis,
C. dubliniensis, and C. albicans are highly pathogenic
Candida species frequently reported to produce SAP [189].
Although non-pathogenic or minimally pathogenic species
possess and express SAP genes, they produce insignificant
quantities of the enzyme.
Lipases
Lipase is one of the enzymes produced by pathogenic
Candida spp. Lipases facilitate lipid digestion for nutrient
uptake (refer to Table 3 for other functions). The enzyme is
also required for initiation of inflammation. This is achieved
by lysing resident microflora within the immediate environ-
ment which affects cells of the immune system [53, 54].
Lipase is a key enzyme that facilitates the hydrolysis of ester
bonds of triglycerides releasing monoacylglycerol (fatty acid)
Eur J Clin Microbiol Infect Dis
and glycerol [196]. There are about 10 members of the lipase
family gene (LIP 1–10). The expression of the genes in human
infection was first shown by Stehr et al. [197] In 2008, Paraje
et al. [198] showed for the first time that lipase produced by
C. albicans triggers cytotoxicity and facilitates lipid deposi-
tion in the cells of the immune system. This attribute is prob-
ably due to the production of ROS. Although lipase produc-
tion was first reported in C. albicans, non-albicans such as
C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis have
all been shown to possess lipase genes orthologous to those
found in C. albicans [199]. Tissue destruction due to
C. parapsilosis infection can be greatly reduced by lipase
inhibitors [200].
Coagulase
Coagulase is not only a differentiation factor in Staphylococci
but also an important virulent determinant in most pathogenic
organisms. Both C. albicans and non-albicans (C. tropicalis)
show coagulase activity with human plasma [201]. The
change in the coagulase activity of Candida species mostly
observed could directly or indirectly provide insight on the
importance of virulence factors in candidiasis. However, the
process involved in the changing of coagulase activity ob-
served in pathogenic Candida species warrants future
research.
Secretion of cytolytic proteins (candidalysins)
Candidalysin, an amino acid peptide, is a cytolytic toxin pro-
duced by C. albicans. A similar cytotoxic protein is also pro-
duced by non-albicans such as C. tropicalis and
C. dubliniensis. Candidalysin is secreted from Ece1p protein.
In C. albicans, the ECE1 is one of the major morphology-
associated genes usually expressed during hyphae formation
[93] (Table 2). Candidalysin has the ability to permeate and
trigger lysis in the host epithelium. It induces a danger re-
sponse signaling pathway and drives epithelial immunity ac-
tivation [58]. It is very crucial for mucosal infection immuno-
pathology. Recently, it was demonstrated that candidalysin is
also required during disseminated systemic infection by
Candida albicans [202].
The production of candidalysin rather than hyphae forma-
tion is one of the indispensable mediators of host cell damage.
This makes it one of the major virulence attributes in Candida
[57]. During C. albicans mucosal infection, damage to the
cells of the epithelium and the overall virulence was greatly
reduced by the removal ECE1 gene [31]. ECE1 mutants form
hyphae akin to the wild-type strain but lack the ability to
damage the cells of the epithelium. Thus, for C. albicans hy-
phae to mediate invasive mucosal infections and enhance
damage to tissues without affecting filamentous growth, it
must be able to secrete candidalysin. This attribute provides
Eur J Clin Microbiol Infect Dis

Table 3 Extracellular hydrolytic enzymes and other virulence factors and molecules in Candida species

S/ Functions References
no.

1 Secretory aspartyl proteinase Facilitates adherence to epithelial host tissues [48]

(SAP) (SAP 1–SAP10)
2 Phospholipase (PLs)
3 Lipase (LP)
4 Hemolysin (HL)
5 Candidalysin (CAL)
6 Adhesins (ADH)
7 Phenotypic switching
8 Superoxide dismutase
(SOD) and catalase
9 Farnesol
10 HSPs
Degrades host tissue proteins [49]
Enhances dissemination
Enhances biofilm formation and phenotypic switching [50]
Protects the fungus against the immune system due to its ability to digest a number of
proteins (complements, cytokines, and immunoglobulin) essential for host defense
Essential for hyphae formation [51]
Digests membrane phospholipids resulting in cell lysis and morphological changes [52]
that facilitate adherence and consequent infection
Facilitates the breakdown of lipids for nutrient assimilation [53]
Enhances adherence to host surfaces
Promotes invasion, mediate interactions with various enzymes, cell signaling and
penetration of infectious particles.
Crucial for initiation of inflammation [54]
Facilitates the degradation of hemoglobin, involved in iron acquisition [55]
Enhances growth, metabolism, and hyphal invasion during infection [56]
Cytolytic peptide toxin encoded by ECE1 gene [57]
Triggers cell lysis or host cell damage and induces epithelial immunity [58]
Promote adherence to surfaces [59]
Mediate colonization and persistence required for biofilm formation [60]
Protects from host immune response and facilitates adaptation in a changing environment [61]
Help to detoxify ROS
Quorum-sensing molecule involved in morphogenesis. [46]
Represses hyphae growth via its effect on signaling cascade involved in morphogenesis. [62]
It controls diverse proteins and TFs involved in hyphae formation.
Involved in biofilm formation and negatively impacts host immune response [47]
Mediate stress responses and involved in morphogenesis [63]
Control several signaling pathways
Regulate diverse cellular processes including biofilm formation [64]
• Hsp 90: Involved in morphological transition, heat tolerance, regulation of cell cycle, [65, 66]
and drug resistance
Controls yeast cell proliferation. Interacts with calcineurin for mycelia to yeast transition to occur. [67, 68]
Elicit the genes that negatively regulate yeast-to-hyphae transition via the Ras1-pka [69]
signaling repression
Downregulation initiates Ras1-pka pathway important for hyphal growth [70]
• Hsp 70: The two members seen in C. albicans are Ssa1 and Ssa2. They trigger endocytosis [43]
of the host cells and exert strong effects on C. albicans virulence. These effects can be positive
or negative.
• Hsp 60: Basically involved in immunological reactions
• Hsp 12 (small Hsp): Enhances cell adhesion, proliferation of yeast cells and decreases [71–73]
C. albicans susceptibility to farnesol
• Hsp 21 (small Hsp): Controls homeostasis of glycogen, glycerol, and trehalose [74]

the link between hyphal development and epithelial damage.
It is now known that the production of candidalysin is a vital
step that enhances mucosal Candida infection and accelerates
disease progression.
According to Ho et al. [203], candidalysin activates innate
epithelial immune responses via the epidermal growth factor
receptor (EGFR). This observation justifies EGFR as a sensi-
tive part of candidalysin-induced immunological response.
Candidalysin triggers the production of lactate dehydrogenase
[93, 204] which indicates damage to the cells and disruption
of the membrane. In addition, candidalysin triggers epithelial
immunity using MAPK signaling molecules which invariably

activates the recruitment of immune cells essential for protec-
tion against mucosal infection [93, 205, 206]. It also triggers
the NLRP3 inflammasome causing cytolysis in phagocytes.
Candidalysin and the associated signaling components are
potential therapeutic targets for treatment of mucosal infec-
tions. Understanding how candidalysin interacts with the cells
of the epithelium prior to damage and infection progression is
very important. Future studies should also look at how
candidalysin is detected by cells of the epithelium. This will
help to better understand the pathogenesis of Candida species
and more importantly pave the way for better therapeutic
approach.
Heat shock protein secretion
Heat shock proteins (Hsps) found in most microbes are usu-
ally induced in response to oxidative and thermal stress, nu-
trient deficiencies, osmotic pressure, and pH stress [67]. They
interact with several signaling pathway regulators which gives
them the ability to control vast number of cellular activities
and virulence factors [23]. Hsps act as molecular chaperons
(proteins that recognize and bind with nascent polypeptides
and partially folded protein intermediates) preventing their
aggregation and misfolding. In dimorphism, expression of
these Hsps is upregulated at the yeast stage.
When signaling pathways are triggered by thermal stress
and other environmental perturbants, the heat shock transcrip-
tion factor (Hsf1) is phosphorylated [207, 208]. The phos-
phorylation of Hsf1 results in the expression of Hsp genes.
The heat shock element (HSE) aids the expression of several
Hsp genes [209]. This gene expression has a high influence on
several cellular processes [23] and overall virulence of
Candida spp. as shown in Fig. 3. Nair et al. reported that
Hsf1 regulates several cellular processes [210]. When induced
by non-thermal stress, Hsf1 regulates key chaperons, controls
genes involved in filamentation. They are also involved in
stress response and resistance to antifungal agents. During
iron starvation, Hsf1 is also very vital for survival [210].
Hsp plays an important role during cellular stress. It interacts
with regulators of several signaling pathways. It is crucial for
yeast growth and the overall virulence of Candida spp. as
specified in Table 3. Disrupting signaling pathways associ-
ated with Hsps could have a great effect on Candida
pathogenesis [65, 211]. By controlling signaling pathways,
Hsps confer antifungal drug resistance [212]. Six HSPs
associated with pathogenesis have been observed in
C. albicans: Hsp 90, Hsp 60, Hsp 21, Hsp 104, Hsp
12, and Hsp 70 [213] (refer to Table 3 for their specific
functions). Based on the available studies, targeting HSP-
related signaling pathways or disrupting the activity of
HSP 90 which happens to be the most frequently
researched heat shock protein is a potential route for de-
veloping new drugs against C. albicans infections [214].
Eur J Clin Microbiol Infect Dis
Adaptation to pH fluctuation
Environmental pH has effects on Candida survival. At opti-
mum pH, proteins function effectively. However, they lose
their activity when there is alteration in pH [215]. This change
in pH disrupts nutrient (e.g., iron) acquisition required for
innate immunity and other vital functions. However, change
in pH triggers signaling pathways (allows the organism to
sense pH alteration) and changes the expression of genes,
PHR1 and PHR2, in Candida species [215]. Controlling ex-
tracellular pH is a vital aspect of fungal physiology necessary
for maintaining fitness within the host. Adaptation to varying
environmental pH is an indispensable factor in Candida
pathogenesis.
In most pathogenic fungi, alkalinity induces morphological
changes, filamentation, and even the production of fruiting
bodies [216]. Most of these physiological processes are criti-
cal for disease progression. Alkalinity enhances invasion of
tissues and helps cells to evade activities of immune cells. In
maintaining internal pH, C. albicans produces ammonia
(NH3). During the process of exporting the NH3 out of the
cell, the NH3 is changed to NH4+ by the action of the enzyme,
urease. Increase in the quantity of the NH4+ within the envi-
ronment increases the pH which has been shown to facilitate
morphogenesis. It also enables the fungus to evade the action
of phagosome and macrophages [217]. Therefore, a dramatic
cytosolic alkalinization in C. albicans precedes hyphal forma-
tion. Studies have shown that Pma1p is the regulator of this
event [218, 219]. About 20–40% of the entire plasma mem-
brane protein is made up of Pma1p. Recently, Rane et al. [220]
suggested that Pma1p, the major regulator of cytosolic pH in
fungi, plays an important role in cytosolic alkalinization and
contributes to growth, pH homeostasis, filamentation, and the
overall increase in C. albicans virulence. The role of Pma1p as
a pH regulator in Candida makes it an important target for
antifungal drugs.
Not minding the role of alkaline pH in Candida virulence,
Candida species can also acidify the environment.
Acidification of the environment allows the secretion of
SAP-potent virulent factor and offers a protective effect to
Candida species. Adaptation and survival of Candida in acid-
ic environment are important for vital cellular activities such
as phenotypic switching, mating, and morphogenesis [221]. In
a media with pH ranging from 2–10, Candida can proliferate
effectively. Studies have isolated Candida in the oral surfaces,
stomach, and vaginal tract with pH of 2, 4–5, and 6 respec-
tively [222]. The cell wall of C. albicans grown in the acidic
environment has a higher level of chitin and β-glucan. The
remodeling of the cell wall due to the acidity results in in-
creased immune cell identification of C. albicans and higher
proinflammatory processes resulting in better colonization.
Finally, the acidity of the vagina contributes to increased re-
sistance to azoles [223]. Lourenco et al. [224] in a contrasting
Eur J Clin Microbiol Infect Dis
Thermal stress
Calcium-calcineurin RAS-cAMP-PKA
Hsf1
Efg1
TFs Hsp 70
Hsp 90
Biofilm formation
Morphogenesis
Cell adhesion
Increased virulence &
pathogenesis
Fig. 3 The activation of heat shock proteins and their role in Candida
pathogenesis. When signaling pathways are triggered by thermal stress
and other environmental perturbants such as oxidative stress and the
presence of heavy metals, the heat shock transcription factor (Hsf1) is
phosphorylated. The phosphorylation of Hsf1 results in the expression of
observation noted that the level of acidity in the vagina regu-
lates C. albicans and C. glabrata sensitivity to the azole anti-
fungal agents. What remains to be fully understood is whether
the presence of acid in the vagina facilitates resistance or sus-
ceptibility to the azole antifungal drugs used in the treatment
of candidiasis. This understanding will help in developing
better therapeutic options for the management of vulvovaginal
candidiasis. In addition, studies on pH signaling pathways in
C. albicans and non-albicans Candida species are clearly
needed.
Efficient responses to multiple stresses
In dynamic environment, stress adaptation is very critical for
microbial survival and effective colonization. For yeast cells
to adhere, multiply, undergo morphogenesis, invade the tis-
sues, and establish infection, they must be able to cope with
multiple stresses. Some of the stress conditions encountered
by yeast cells can be categorized into oxidative stress, osmotic
stress, nutrient stress, thermal stress, and even pH-related
stress. Host defense mechanisms are also perceived as a form
of stress. Generally, immunological response can release reac-
tive oxygen species (ROS) leading to oxidative stress and can
even create a nutrient-deprived environment for yeast cells.
Oxidative stress
Non-thermal stress Osmotic stress Environmental perturbants
Nutrient stress
Heavy metals
MAPK pathways
P
Hsf1
Hsp 21 Heat shock proteins (HSPs)
Hsp 60 Hsp 12
Thermotolerance
Resistance to antifungal drugs
Hsp genes. The heat shock element (HSE) aids the expression of several
Hsp genes. The signaling pathways also induce the Efg1 gene and several
TFs including those involved in biofilm formation and hyphae formation.
This gene expression has a high influence on several cellular processes
which ultimately result in increased virulence and pathogenesis
Immune response can also secrete proteins that are very lethal
to Candida spp. The recruitment of neutrophils, basophils,
cytokines, chemokines, and even the complement proteins
can reduce the chance of proliferation, tissue invasion, and
the survival chances of pathogens. Notwithstanding, microbes
must find a way to survive.
Most pathogenic Candida spp. have evolved efficient
stress response mechanisms while new mechanisms keep
emerging in response to ever-fluctuating environmental con-
ditions. Candida responds to various stress inputs using spe-
cific signaling pathways such as MAPK, Hog1, and Mkc1
pathways (refer to Table 1). Cap1, Skn7, and Msn4 are some
of the transcription factors that drive stress response in
Candida [30]. In C. albicans, the Hsf1, Cta4, Cap1, and
Skn7 are actively involved in resistance to thermal,
nitrosative, and oxidative stress conditions. Cell wall remod-
eling, fatty acid metabolism, and response to oxidative stress
have an association with cationic stress [225]. Ribosomal bio-
genesis reduction and glycerol accumulation are part of the
requirement for survival in high NaCl environment [226].
There is also a reduction in translation.
Most pathogenic Candida spp. are less likely to survive in
any environment with high prevalence of cationic and oxida-
tive stress [227]. In the presence of cationic stress, Candida

upregulates ORF19.7296 transcription but requires Hog1p
and Sko1p (HOG signaling components) for full expression
[225]. The ORF19.7296p is found in the plasma membrane
and together with SLP3 make up C. albicans genome [228].
Diverse environmental stress triggers an increase in SLP3 ex-
pression. Under stress conditions and in the presence of high
concentration of NH4+, SLP3 transcription is upregulated
[229]. However, SLP3 is downregulated during yeast-to-
hyphae transition and exposure to thermal stress [230]. SLP3
was found to be an important gene mediating stress response
factor in the yeast phase but not in hyphal phase [228].
Reduction in the quantity of short-chain fatty acids, derived
from fungi due to antibiotic elicited stress, results in a rise in
C. albicans colonization of GIT [231]. Therefore, therapeutic
approaches that augment host defense can be developed by
understanding of stress response mechanisms.
Genome plasticity
Candida albicans is a highly heterozygous diploid species
with a high level of genomic and genetic variability among
clinical isolates. Candida also shows an unusual ability to alter
its genome, adapt and survive in an ever-fluctuating environ-
ment [33]. Different genotypes and strains of Candida
albicans exhibit different virulence activities [186]. Changes
in genetic composition under fluctuating environmental con-
ditions trigger pathogenicity [232]. Genome plasticity has sev-
eral effects on virulence and pathogenicity of Candida species
(Table 1). Dunn et al. [233] reported that genetic diversity
associated with the massive increase in TLO gene family,
encoding the Med2 subunits, influences a range of pheno-
types. It also contributes to C. albicans commensalism and
its switch to an opportunistic pathogenic strain.
Therefore, exposures to host environment, antifungal
drugs, DNA transformation, oxidative stress, temperature, nu-
trient stress, and osmotic stress induce and elevate large scale
chromosomal changes that lead to genome plasticity. Genes
mediating virulence and pathogenicity in most pathogenic
fungi are highly clustered in variable and physically distinct
genome compartment. Phenotypic variation in addition to host
specificity, pathogenicity, antimicrobial resistance, and viru-
lence in pathogenic Candida species may be explained by
genetic diversity and genome organization.
Adherence to surfaces
Adherence to host surfaces is a primary event in candidiasis. It
is required for initial colonization and persistence prior to
initiation of infection. Adherence is controlled by proteins
termed adhesins [59]. The ALS gene is responsible for the
most common adhesins in C. albicans (Table 2). Eight sets
of ALS genes encode the glycoproteins of which ALS-3 ap-
pears to be the most important [150]. Hwp1 is also one of the
Eur J Clin Microbiol Infect Dis
most important adhesins [234]. Some proteins that are not
adhesins such as Cbk1, Svn41, and Pga1 also control adher-
ence [89, 235]. During infection of the mucosal epithelium,
Als-3 is upregulated. Als-3 also plays an important role during
biofilm formation as it helps cells to adhere to each other
[236].
Antifungal resistance
Resistance to antifungal drugs, especially the azoles, is gener-
ally attributed to changes in the expression of ERG11 gene,
and alterations or mutations in ERG biosynthesis. It is specif-
ically due to the overexpression of the ERG11 which increases
ERG11 enzyme copy number. The upregulation or overex-
pression of the multidrug transporter also enhances resistance
to antifungal drugs. Resistance to antifungal agents is one of
the pathogenic determinants of Candida spp. because of the
ability of the resistant cells to persist, survive, and establish
infection.
Table 3 summarizes the essential virulent factors and their
roles in Candida pathogenicity while Fig. 1 shown in the
previous section outlines the major network of Candida viru-
lence and pathogenesis. It shows the connections between the
various determinants of pathogenesis and virulent factors
discussed in this review.
Conclusion/recommendation
This review has shown that several transcriptional factors,
metabolic pathways, morphology-associated/virulence
encoding genes, biofilm formation, phenotypic switching,
host microbiota composition, and a host of other virulence
features are indispensable factors required for virulence and
pathogenicity in Candida species. Targeting the various path-
ogenic routes represents a very vital way for the formulation
of novel antifungals. Much have been learned in the under-
standing of Candida pathogenesis mechanisms as shown by
the plethora of published data illustrating modern therapeutic
approaches. It is unequivocally clear that in order to formulate
new antifungals or increase the efficacy of the already avail-
able ones, develop novel vaccines, and efficiently control can-
didiasis, significant advances in the understanding of the di-
verse routes and regulatory mechanisms of Candida pathoge-
nicity are indispensable. The following conclusions (key
points) and recommendations extracted from our study can
be made:
1. There still remain considerable gaps in our knowledge of
the exact mechanism that triggers Candida transition
from yeast to hyphae. To better understand this, more
attention should be given to yeast promoting regulators.
Eur J Clin Microbiol Infect Dis
2. Targeting signaling pathways may be a powerful strate-
gy in preventing fungal virulence. Anti-virulence com-
pounds that could target morphogenesis and other im-
portant signaling pathways could be a very possible al-
ternative or contribution to the current armamentarium
of antifungal drugs. Identification of alternative physio-
logical pathways of central metabolism that affect path-
ogenicity is very necessary. In addition, the roles of these
pathways in the pathogenesis of non-albicans Candida
species need to be fully explored and elucidated.
3. The induction and repression of morphology-associated
genes are regulated by several factors including TFs.
However, more still remains to be learned on how these
activities are linked to the genetic programs controlling
morphogenesis.
4. Just as hyphae initiation and formation are important, its
extension, formation of tip, and branching need to be
thoroughly investigated as they might be as important
as hyphae initiation in the pathogenicity process.
5. Changes in the host microbiota composition generate
diversity among Candida species. How this facilitates
the transition from commensalism to pathogenicity still
needs to be fully understood.
6. More insights on the interaction between immune cells,
resident microbiota, and Candida spp. are still needed.
There is need to pay attention to the non-albicans
Candida spp. interactions with resident microbiota in-
cluding interactions among Candida species.
7. Analysis of the various adaptive responses in Candida
that contribute to pathophysiology of candidiasis is im-
portant. To more accurately mimic human host condi-
tions, in vitro experimental conditions should be effec-
tively altered.
8. Environmental pH is very vital for survival. Acidic envi-
ronments regulate key biological processes. However, it
remains to be fully understood whether the presence of
acids in the vagina facilitates resistance to the azoles used
in treatment or enhances susceptibility to antifungal agents.
9. It is clear from published studies that in response to fluctu-
ating environmental conditions, Candida species can swap
between different morphological phenotypes. Questions
pertaining how pathogens adapt and survive under diverse
environmental conditions can be answered by understand-
ing the control mechanisms involved in phenotypic
switching. However, there are still questions on why
C. albicans integrate morphological switch as part of its
sexual life cycle. In addition, whether white-opaque
switching and phenotypic switching systems as well as
their various mechanisms of regulation are real representa-
tion of events in the human hosts are still unclear.
10. Research studies centered on the development of vac-
cines that target the major virulence factors in Candida
species are highly needed.
11. Finally, continued progress in the understanding of the
mechanisms of Candida pathogenicity will contribute
immensely in the management of candidiasis.
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