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REVIEW
Current Aspects in the Biology, Pathogeny, and
Treatment of Candida krusei, a Neglected Fungal
Pathogen
This article was published in the following Dove Press journal:
Infection and Drug Resistance
Manuela Gómez-Gaviria
Héctor M Mora-Montes
Departamento de Biología, División de
Ciencias Naturales y Exactas, Campus
Guanajuato, Universidad de Guanajuato,
Guanajuato, Gto, México
Abstract: Fungal infections represent a constant and growing menace to human health,
because of the emergence of new species as causative agents of diseases and the increment of
antifungal drug resistance. Candidiasis is one of the most common fungal infections in
humans and is associated with a high mortality rate when the fungi infect deep-seated
organs. Candida krusei belongs to the group of candidiasis etiological agents, and although
it is not isolated as frequently as other Candida species, the infections caused by this
organism are of special relevance in the clinical setting because of its intrinsic resistance
to fluconazole. Here, we offer a thorough revision of the current literature dealing with this
organism and the caused disease, focusing on its biological aspects, the host-fungus interac-
tion, the diagnosis, and the infection treatment. Of particular relevance, we provide the most
recent genomic information, including the gene prediction of some putative virulence factors,
like proteases, adhesins, regulators of biofilm formation and dimorphism. Moreover,
C. krusei veterinary aspects and the exploration of natural products with anti-C. krusei
activity are also included.
Keywords: virulence, candidiasis, host-fungus interplay, antifungal drug, immune sensing
Introduction
Candidiasis is the infection caused by members of the fungal genus Candida,whichcan
beasuperficial or a deep-seated disease. The latter is often associated with high
morbidity and mortality rates, in particular in hospitalized or immunosuppressed patients.
Arateof3–28 patients out of 1000 intensive care unit admissions in European hospitals
develop candidemia;
1
and in the United States of America the scenario is similar, as the
Transplant-Associated Infection Surveillance Network reported that 3.8% of solid organ
transplant recipients developed invasive candidiasis.
2
Studies that have enrolled cancer
patients admitted into hospitals placed in Europe or the Middle East showed a 36–39%
mortality rate after one month of hospitalization,
3,4
and these figures suffer minor
modifications when the mortality associated to systemic candidiasis among intensive
care unit patients is analyzed, which has been calculated in 48%.
5
This rate though can
scale to figures in the range of 63–75%, depending on the hospital and the patient’s
staying ward.
6
Thus, there is no doubt that candidemia represents a global healthcare
problem and a significant burden on patients.
Candida albicans is the most frequent etiological agent of candidiasis, although
other Candida species are also relevant in the clinical setting, causing about 35–65%
Correspondence: Héctor M Mora-Montes
Departamento de Biología, División de
Ciencias Naturales y Exactas, Campus
Guanajuato, Universidad de Guanajuato,
Noria Alta s/n, Col. Noria Alta, C.P. 36050,
Guanajuato, Gto, México
Tel +52 473-7320006 Ext. 8193
Fax +52 473-7320006 Ext. 8153
Email hmora@ugto.mx
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of candidemia cases.
7,8
These include Candida tropicalis,
Candida parapsilosis, Candida glabrata, Candida guillier-
mondii, Candida dubliniensis, Candida auris,andCandida
krusei.
6,9
Collectively, these species are the causative agents
of non-albicans candidiasis and infections by C. krusei are
characterized because of their high mortality rate (40–58%)
and poor response to standard antifungal therapies.
10,12
Due to the clinical relevance of this organism and the
significant amount of information generated in recent years;
here, we provide a literature revision on the C. krusei basic
and clinical aspects.
Biological and Fungal Aspects
C. krusei produces cylindrical yeast cells that may have up
25 µm of length (Figure 1). They usuallyresemble long-grain
rice, which contrasts with the spheric or ovoid shape of other
Candida species.
13
Like C. albicans, C. krusei shows ther-
modimorphism, producing hyphae when growing at 37°C
and blastoconidia and pseudohyphae when incubated at
lower temperatures (Figure 1).
14,15
The colony morphology
is the typical one of other Candida species, with no obvious
features that could provide a hint about the species: round,
creamy, and smooth whitish colonies of about 5–8mmdia-
meter when grown at 25–28°C in rich culturing media, such
as malt yeast extract glucose agar, yeast extract peptone
glucose agar, or Sabouraud agar (Figure 1). Even though
colony morphology switching has been reported,
13
no sys-
tematic attempt to classify the morphological variations has
been reported, like those in C. parapsilosis, C. tropicalis,and
C. albicans.
16–18
One interesting contrast with other medi-
cally relevant Candida species is the presence of sexual
reproduction in C. krusei,beingIssatchenkia orientalis the
teleomorph.
13
Like other fungal cells, a cell wall, intracellular vesicles,
endoplasmic reticulum, mitochondria, ribosomes, and intra-
cellular glycogen-like granules have been described when
cells are inspected under transmission electron microscopy.
19
Importantly, the microscopical examination indicates that
these are mononuclear cells.
19
Thus far, the study of the
C. krusei organelles has not been reported in detail, with
the exception of the cell wall. This bias in the study of
C. krusei components is likely to be related to the relevance
of this structure during the interaction with the host and
because it is a target of some antifungal drugs, as revised in
the following sections. The early study of the C. krusei cell
wall by transmission electron microscopy showed the pre-
sence of three major layers: the outermost is an electron-
dense layer that includes flocculent material surrounding the
cell, followed by an electron-transparent layer in the middle
with the appearance to be composed of fluffy material and
scatter granules, and an innermost electron-denselayer closer
to the plasma membrane.
19
Recently, our group characterized
the basic components of the C. krusei cell wall and found that
contains the same polysaccharides found in the C. albicans
wall: chitin, β-glucan, and mannans.
20
Even though both
species have similar levels of cell wall β-glucan, the chitin
content is a 4.1-fold higher in C. krusei than in C. albicans,
and mannan is 34% less abundant in C. krusei when
Figure 1 Candida krusei cell and colony morphology. (A) Yeast cells were grown in YPD broth until reach the exponential phase and then stained with calcofluor white, to
label chitin. Scale bar = 10 µm. The arrowheads indicate the mother cells. (B) Cell filamentation was stimulated in RPMI medium incubated at 37°C. Scale bar = 20 µm. (C)
AC. krusei colony grown on a YPD plate. Scale bar = 5.0 mm. Images from panels A and B were taken with a Zeiss Axioscope-40 microscope and an Axiocam MRc camera.
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compared to the C. albicans mannan content.
20
In agreement
with this observation, the cell wall protein content, and
O-linked and N-linked mannans decorating the C. krusei
wall glycoproteins were lower than those found in
C. albicans.
20
The structural study of the C. krusei N-linked
mannans indicated that the outer chain is short and lightly
branched with α-1,2-mannose units,
21
which supports our
observations and contrasts with the structure of the
C. albicans N-linked mannans, where the outer chain is
highly branched with α-1,2-mannose units and capped with
either α-1,3-mannose or β-1,2-mannose residues.
22
In regard
to the C. krusei O-linked mannans, these are oligosaccharides
composed of α-1,2-mannose units that can contain from two
to four sugar residues,
23
which again contrasts with the
O-linked mannans found on the C. albicans surface, that
may contain up to seven α-1,2-mannose residues.
24
Like
other Candida species, the C. krusei mannans are modified
with mannose residues bound via phosphodiester links,
named phosphomannan, although the content of this is
about the half of the phosphomannan found in the
C. albicans cell wall.
20
Like in other Candida species, the C. krusei structural
polysaccharides chitin and β-1,3-glucan are localized
underneath other cell wall components, and this impairs
the proper sensing of these polysaccharides by the host
immunity.
20
Thus far, only one report dealing with the C. krusei cell
wall proteome has been reported, but this was performed
with walls from cells growing in the presence of oxidative
stressors.
25
Interestingly, only moonlighting proteins were
identified, which could be a result of contaminants from
intracellular compartments, since cells were disrupted with
an ultrasonic homogenizer.
25
Nonetheless, the presence
and abundance of canonical cell wall proteins found in
other Candida species remain to be established.
The metabolism of this fungal species is another aspect
poorly studied to date. This yeast cell is capable of using
exclusively glucose as carbon source,
13
which is a trait
exploited in its identification by zymograms and chromo-
genic culturing media.
26
This has also been taken in
advantage to produce and accumulate glycerol in fermen-
tative processes with potential industrial applications,
27
and to prepare traditional meals and alcoholic beverages
used by some African communities.
28,29
The fermentation
process involving C. krusei is positively affected by the
presence of lactic acid bacteria, which promote tolerance
to short-term changes in the extracellular pH.
30
Interestingly, and contrary to this restricted carbohydrate
assimilation, C. krusei has been isolated from the decaying
wood from Ficus religiosa; suggesting this could be an
environmental niche of this fungal species.
31
Even though
arabinitol is produced by many yeast-like cells and the
presence of this metabolite has been reported in serum
from patients with invasive candidiasis, C. krusei is incap-
able of producing this five-carbon polyol.
32
In regard to the C. krusei genome, it has been reported
this species does not belong to the CUG clade of the
Candida genus, it is a diploid and heterozygous organism,
with the genetic information distributed in five
chromosomes.
33–35
The C. krusei genome sequence of
a clinical isolate (strain 81-B-5) showed that the nuclear
genome sequence size is 10.9 Mbp, the mitochondrial
genome contains 51.3 kbp, the single nucleotide poly-
morphism rate was calculated in 1/340 bases, being higher
than that reported for C. albicans isolates.
36
Moreover, it
was reported a GC content of 38.42%, a 2.15% of repeat
content with no significant similarity to the repeat
sequences found in C. albicans, and a total of 4949 pro-
tein-encoding genes.
33,35
The number of intron-containing
genes in the coding regions was calculated in 205.
35
Different from other Candida species where high varia-
bility in the mating loci has been reported,
36
these sub-
telomeric loci are complete in C. krusei.
33
A recent study
reported the sequencing of 32 strains of C. krusei, Pichia
kudriavzevii, Issatchenkia orientalis, and Candida glycer-
inogenes and found that they are the same species with
more of 99% identical DNA sequences.
35
Since the ana-
lysis of single nucleotide polymorphisms could not segre-
gate between clinical and environmental strains, it was
suggested that infections by C. krusei are acquired from
the environment.
35
Finally, the analysis of the genome
sequences supported the re-classification of these organ-
isms in the Pichia genus, being a distant relative of the
Candida species.
35
Recent Understanding of the
Host-Pathogen Interaction
Virulence Factors
Since C. krusei and C. albicans belong to the same tax-
onomical genus, it has been assumed they share biological
traits that help them to interact with the host, a wrong
rationale that applies not only to C. krusei but other
medically relevant non-albicans Candida species.
20,37-39
Therefore, the study of C. krusei virulence factors is
a research area with limited information, if compared
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with the vast amount of reports dealing with C. albicans
virulence. In this section, we will provide the most rele-
vant information about C. krusei virulence factors and
a genomic comparison to predict putative orthologs of
well-known factors already described in C. albicans.
Virulence is classically determined by the ability to
damage cells, tissues, organs, or a whole organism, and
in mycology, both the in vitro and in vivo systems are
thoroughly used. In the murine model of systemic candi-
diasis, C. krusei was incapable of killing both female or
male mice, contrasting with the high mortality rate asso-
ciated with C. albicans.
40,41
When the colony-forming
units of these organisms were analyzed in infected spleen,
liver, kidneys, and lungs, a gradual reduction in the
C. krusei burden was observed during the observation
period, with a fungal clearance at day 21 post-infection,
contrasting again with the fungal loads in C. albicans-
infected organs, which were constants or slightly reduced
during the same observation period.
40
Therefore, C. krusei
displays lower virulence than C. albicans in the murine
model of systemic candidiasis. This in vivo system is
regarded as the gold standard to assess the virulence of
Candida species and isolates, but in recent years, logistical
issues to include large numbers of animals per experimen-
tal condition and the increased ethical concerns about the
use of these animals in basic research have limited their
inclusion in the experimental design and stimulated the
search for alternative models to study fungal virulence.
Caenorhabditis elegans is an invertebrate model that has
been used as an alternative for studying the Candida
species virulence.
42
Upon administration of fungal cells
by feeding, C. krusei and C. albicans showed similar
ability to kill C. elegans and were ranked as the most
lethal species in this experimental setting.
42
Like
C. albicans, C. krusei was capable of producing aspartyl
proteinases, phospholipase, hemolysins, and to develop
biofilms, providing a possible explanation to the lethal
behavior in the C. elegans system.
42
Moreover, this inver-
tebrate model has been useful in establishing the effect of
the antibacterial drugs cefepime, imipenem, meropenem,
and vancomycin on Candida spp. virulence. C. albicans,
C. parapsilosis, C. krusei, and C. tropicalis incremented
the proteolytic activity and killing of C. elegans upon
incubation with these drugs, whereas amoxicillin poten-
tiated the virulence of C. krusei and C. tropicalis.
43
The
wax moth Galleria mellonella has been proved as a good
model to study infections caused by C. krusei. Upon
injection into the hemocele, fungal cells decreased
hemocyte density, induced melanization and animal
dead.
44
The virulence in this host is similar to that
observed in the murine model, with C. krusei showing
low to moderate ability to kill G. mellonella (median
survival of larvae was 7 days), which contrast with the
high mortality associated with C. albicans infection (med-
ian survival of larvae was 2 days)
45
In addition, these
larvae have helped to propose that Lactobacillus paraca-
sei, Lactobacillus fermentum, and Lactobacillus rhamno-
sus, acid bacteria used as probiotics, have a prophylactic
effect on the larvae, increasing the animal survival upon
administration of a C. krusei lethal dose.
46
Drosophila
melanogaster is another invertebrate model that has been
used to evaluate the C. krusei virulence. Adult flies with
mutations in the toll signaling pathway were highly sus-
ceptible to infection with either C. albicans or C. krusei,
demonstrating this model is useful for virulence
assessment.
47
Moreover, these data strongly suggest that
C. krusei lethality depends on the immunological status of
the host, as in immunocompetent animals this Candida
species was not capable of killing the host.
40,41
Cell and tissue adhesion are part of the early stage of the
Candida-host interaction and will lead to the establishment
of both commensalism and pathogenesis. Adhesion is para-
mount to establish colonization and tissue invasion in the
oral epithelium, as this tissue is in constant contact with
saliva, which cleans the epithelial surface. C. krusei binds to
human buccal epithelial cells but not as efficient as
C. albicans and C. tropicalis.
48
Accordingly, exposure of
the epithelial cells to the minimum inhibitory concentration
of nystatin affected the Candida species adhesive proper-
ties, with C. krusei showing a 64% reduction of adhesion to
epithelial cells, a value higher to that found in C. albicans
(54%).
48
Similar to epithelial cells, endothelial cells are also
a surface where C. krusei can adhere, but not as efficiently
as C. albicans.
49
In agreement with these observations,
C. krusei showed 11-fold lower colonization potential of
the rat oral surface than C. albicans.
50
However, C. krusei
adheres in great numbers to acrylic surfaces.
50
Interestingly,
when the C. krusei phenotypical switching was induced
with phloxine B, a 30-fold increment in adhesion to saliva-
coated glass surface was observed.
51
The Eap1, Iff4, Mp65,
Phr1, Int1, Ecm33, and ALS gene family members are the
major C. albicans adhesins.
52–58
The putative functional
orthologs of the genes encoding for Phr1 and Int1 were
identified within the C. krusei genome but no those encod-
ing for Eap1, Iff4, Ecm3 or any of the Als family members
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(Table 1). Interestingly, three putative orthologs of
C. albicans Mp65 were identified (Table 1).
The cell wall hydrophobicity is an important aspect of
interaction with the host components. A study that
involved 20 C. krusei isolates showed these had higher
wall hydrophobicity than C. albicans cells, and there was
a correlation between hydrophobicity and adhesion to
HeLa cells, but not to acrylic surfaces.
59
Several studies have demonstrated that C. krusei, like
other Candida species, is capable of secreting hydrolytic
enzymes that could degrade host macromolecules, contribut-
ing to nutrient acquisition, to degrade immune effectors, or in
the dissemination within the host tissues. In two independent
studies, using clinical isolates, C. krusei did not show phos-
pholipase activity, contrasting with C. albicans strains that
had a strong presence of this enzyme activity.
60
However,
other studies have shown that this enzyme activity is found in
C. krusei.
61–63
Whether this discrepancy is due to different
methodologies used to measure phospholipase activity or
reflects the phenotypical plasticity of the species remains to
be addressed. Nonetheless, the C. krusei genome contains
two putative orthologs of the PLB gene family that encodes
for the major C. albicans secreted phospholipase activity
(Table 1).
64,65
Interestingly though, no putative orthologs of
the genes encoding for secreted lipases belonging to the
C. albicans LIP gene family
66
were found within the
C. krusei genome (Table 1).
Other hydrolytic activities like proteinase, hemolytic
factors, and DNase have been reported in C. krusei.
60,67,68
A study that included clinical isolates from Turkish patients
diagnosed with candidiasis, found that about half of the
C. krusei isolates formed biofilms, 22% showed coagulase
activity and all the isolates were capable of hemolyzing red
blood cells.
69
In C. albicans, most of the secreted
Table 1 Prediction of Some Virulence Factors in Candida krusei
Virulence Factor C. albicans Gene C. krusei Gene* E value** Similarity (%)**
Adhesins EAP1 No found ––
IFF4 No found ––
MP65 ONH75632 5e
−118
66
ONH70941 1e
−68
55
ONH73292 8e
−42
55
PHR1 ONH72606 0.0 72
INT1 ONH72359 2e
−57
53
ALS No found ––
ECM33 No found ––
Secreted hydrolases PLB1-PLB5 ONH77577 1e
−166
61
ONH74522 2e
−88
51
LIP5 or LIP8 No found ––
SAP1 –SAP5 ONH77652 2e
−39
47
ONH72963 4e
−22
45
ONH70287 2e
−22
42
ONH77630 5e
−20
46
ONH77640 7e
−10
55
Biofilms HSP90 ONH74083 4e
−123
92
BCR1 ONH74628 8e
−29
70
EFG1 ONH73730 9e
−66
92
ROB1 No found ––
BRG1 OUT23966 9e
−21
67
ZAP1 OUT21350 2e
−59
52
Dimorphism HGC1 AWU73609 4e
−16
45
NRG1 ONH70717 1e
−27
64
TUP1 ONH77322 0.0 67
CPH1 OUT20780 2e
−79
59
Notes: *Gene nomenclature corresponds to accession codes of the GeneBank database (https://www.ncbi.nlm.nih.gov/genbank/). **When comparing the encoded protein
of C. krusei gene with the putative ortholog in Candida albicans.
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proteolytic activity is associated with members of the SAP
gene family.
70,71
A search for putative orthologs of mem-
bers of this gene family in C. krusei identified SAP1-SAP5,
but not SAP6-SAP10 (Table 1). These genes are likely to
account for the secreted proteolytic activity reported in
C. krusei clinical isolates.
C. krusei is capable of forming biofilms on polyethy-
lene, polyvinylchloride, and glass.
67,72
These fungal bio-
films are particularly sensitive to fluconazole when
generated on polystyrene surfaces.
73
This represents
a promising observation that remains to be confirmed
in vivo. In agreement with the reported ability to generate
biofilms, the C. krusei genome contains key genes involved
in the establishment of these multicellular communities.
The chaperone Hsp90, besides contributing to the establish-
ment of apical growth during the C. albicans dimorphism, is
required to neutralize the cellular stress generated during
biofilm formation;
74
while Efg1, Brg1, Zap1, and Bcr1 are
transcriptional factors required for biofilm formation in
both in vitro and in vivo conditions.
75–77
Putative orthologs
for these genes were found within the C. krusei genome
(Table 1). However, for the case of Rob1, a transcriptional
factor required for biofilm formation in C. albicans,
76
no
putative ortholog was found within the C. krusei genome
(Table 1), suggesting that the regulatory network of biofilm
formation in both organisms could share master regulators
but their contribution might be species-specific.
As mentioned, C. krusei belongs to the members of the
genus capable of forming true hyphae. The C. albicans
dimorphism has been associated with tissue invasion and
the expression of several virulence factors that are mor-
phology specific.
78
The Hgc1 is a hypha-specific G1 cyclin
essential for the establishment of the apical growth and is
negatively regulated by the transcriptional repressors Nrg1
and Tup1; while Cph1 and Efg1 are transcriptional factors
required to sustain hyphal growth.
79–81
The C. krusei gen-
ome contains putative orthologs of these genes (Table 1),
suggesting the central regulatory network that controls
dimorphism is similar in both species.
In this regard, it is noteworthy to mention that C. krusei is
capable of inhibiting the C. albicans filamentation and biofilm
formation.
82
Even though there is no formal explanation yet
for these observations, the production of signaling molecules
by C. krusei to avoid polarized growth in C. albicans,compe-
tition for nutrients, adherent surfaces, and space between the
biofilms are the main hypotheses currently under study.
82
Gliotoxin is an immunosuppressive compound from the
fungal metabolism and has been suggested as a fungal
virulence factor, including in C. albicans.
83
However,
a chemical analysis based on highly sensitive HPLC and
tandem mass spectrometry of 100 clinical isolates of
Candida spp, including C. albicans and C. krusei did not
detect intracellular or extracellular gliotoxin production, sug-
gesting this compound does not participate in the pathogen-
esis of Candida spp.
83
In the same line, the C. albicans
cytolytic peptide toxin named candidalysin, which is essen-
tial for mucosal infection and encoded by ECE1,
84
has no
putative ortholog within the C. krusei genome.
It is noteworthy to mention that C. krusei has been iso-
lated from bat feces in a Brazilian urban region, and showed
the ability to secrete proteases, to form biofilms, and kill
laboratory animals, suggesting the animal depositions could
be an environmental source for C. krusei infections.
85
Similarly, C. krusei has been isolated from droppings of
healthy breeding rheas, chickens and hens,
86,87
and from
the vestibule and vagina of healthy female horses.
88
The C. krusei-Immune System Interaction
Similar to other pathogens, the C. krusei recognition and
interaction with components of the host immunity is required
to establish a response that could protect against the infec-
tion. Both the innate and adaptive branches of immunity are
essential to control fungal pathogens, including C. albicans
and other causative agents of candidiasis.
89,90
As part of the humoral factors that belong to the innate
immunity, some cells produce antimicrobial peptides that
show antifungal properties. The human β-defensin 2 is
produced by epithelial cells, while the human neutrophil
peptides 1–3 are α-defensins synthesized by circulating
white blood cells.
91
Both kinds of antimicrobial peptides
were stimulated by C. albicans and C. krusei, being the
former a stronger inductor than C. krusei cells.
91
With no
doubt, this study showed the ability of C. krusei to stimulate
both local and systemic responses against this pathogen.
Similarly, it was reported that C. krusei is 1.4 times more
sensitive to lactoferrin, a secreted antimicrobial protein,
than C. albicans cells; and this difference has been sug-
gested to be relevant to modulate the fungal oral carriage.
92
The peripheral blood mononuclear cells (PBMCs) are
a heterogeneous group of immune cells with the ability to
produce cytokines upon the interaction between pathogen-
associated molecular patterns and their pattern recognition
receptors.
Different to the human PBMCs-C. albicans interaction,
where low levels of TNFα, IL-6, IL-1β, or IL-10 were
stimulated, the immune cells interacting with C. krusei
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produced higher levels of these four cytokines.
20
Both
C. albicans and C. krusei heat-killed cells, which expose
inner wall components like β-1,3-glucan and chitin at the
cell surface, stimulated higher levels of TNFα, IL-6,
IL-1β, or IL-10, when compared to live cells.
20
Interestingly, a difference between C. krusei and
C. albicans was observed when O-linked mannans were
removed from the cell wall: C. albicans recognition by
PBMCs was not affected, indicating this wall component
is dispensable for cytokine stimulation; while in C. krusei,
cells with no O-linked mannans on the surface were cap-
able of stimulating higher cytokine levels, most likely
because of the unmasking of β-1,3-glucan and increased
recognition via dectin-1.
20
Like in C. albicans, this
immune receptor is essential to control C. krusei infec-
tions, as dectin-1 knock out mice are more susceptible to
C. krusei and showed poor ability to establish a protective
anti-C. krusei immunity.
93
In contrast with C. albicans cells, C. krusei yeast cells
induced lower levels of complement components C3 and
factor B, and the granulocyte-macrophage colony-
stimulating factor, but a significant amount of IL-12
(p70).
94,95
This differential ability to stimulate IL-12 (p70)
could be part of the C. albicans strategies to avoid the estab-
lishment of an effective type I immune response against this
pathogen, a situation likely to occur fo the case of C. krusei.
94
Contrary to this observation though, C. albicans is
more readily phagocytosed by neutrophils than C. krusei
cells (37% vs 9%),
96
and more susceptible to the neutro-
phil-expressed antimicrobial protein S100A12 than
C. krusei,
97
underscorings that the differences in patho-
genicity and control by the innate immune system are
difficult to be reduced to the analysis of a handful of
biological parameters.
Like other pathogens, C. krusei is capable of interact-
ing with macrophages, but interestingly the outcome is
variable. Rat alveolar macrophages phagocytosed
C. glabrata and C. albicans in a similar rate, but this
was significantly slower for the case of C. krusei, due to
reduced attachment.
98
This differential recognition was
abrogated though when the fungal uptake was performed
with opsonized cells.
98
For the case of primary human
PBMC-derived macrophages, the results are the opposite:
C. krusei is more readily phagocytosed than C. albicans,
C. auris, C. tropicalis, and C. guilliermondii.
20
In mice,
both a macrophage-like cell line and primary macrophages
are capable of uptaking C. krusei yeast cells, with around
10 to 20% of the immune cells ingesting yeasts after 2 h,
without opsonization.
99
However, C. krusei was capable of
surviving and undergoing filamentation inside the phago-
cytic cells, induced defects in the phagolysosome matura-
tion, yeast transfer between infected macrophages,
macrophage fusion, and death of the immune cells.
99
These data clearly show that the origin of the immune
cells has to be taken in to account before drawing general
conclusions.
Pyroptosis, an inflammasome-mediated macrophage
death process, is activated upon interaction with
C. albicans cells.
100
This caspase-1-, ASC-, and NLRP3-
dependent pathway is triggered in lower levels by C. krusei
cells and does not restrict the fungal replication.
100
The interaction between C. krusei with dendritic cells
has particular outcomes too. The C. krusei mannan but not
the cell wall component isolated from C. albicans,
C. tropicalis or C. glabrata induced strong cytokine pro-
duction by these immune cells and led to apoptosis.
101
These effects on dendritic cells were mediated by TLR2
and activation of a MyD88-dependent pathway, which
controlled the production of the polarizing cytokines IL-
12 and IL-6, and thus the Th1/Th17 switching.
101
Interestingly, human PBMCs tend to proliferate in the
presence of either voriconazole or caspofungin and pro-
duce increased levels of IL-2, IFN-γ, and IL-6 when sti-
mulated with either C. albicans or C. krusei, with no effect
on the stimulation of TGF-βand IL-10.
102
These data
suggest that antifungal therapy has a positive immunomo-
dulatory effect on human PBMCs, an observation that
should be further explored and taken into account during
the treatment of candidiasis and other fungal infections.
Another promising study on new immunomodulatory
approaches for the treatment of candidiasis caused by
C. krusei involves chromogranin A, a mammalian-
expressed soluble protein of the adrenal medullary chro-
maffin granules and neurons. Chromogranin A N-46, a 46
amino acid portion of the chromogranin A N terminal has
shown to have antifungal properties.
103
In line with this
observation, treatment with this peptide (60 mg/kg/day)
had positive effects on mice infected with C. krusei.
Treated animals showed increments in the body weight
and survival, along with higher counts of circulating
monocytes, lymphocytes, and neutrophils.
103
Candidiasis Caused by C. krusei
The list of the etiological agents of candidiasis is vast and
new species have been added in recent years; however,
most of the cases are caused only by five species, named
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C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and
C. krusei.
104
Even though C. albicans is the most common
cause of candidemia worldwide, infections caused by
C. krusei are an emergent public health threat. Data from
the ARTEMIS DISK registry gathered from 1997 to 2007
indicated that the frequency of C. krusei-associated infec-
tions was stable, ranging from 1.7 to 3.2%.
104
A report from a tertiary care academic hospital in
Montreal, which included 190 cases of candidemia,
found that C. krusei was the causative agent in 7% of the
patients, but this increased up to 13% in the period of
2003–2006.
105
The most likely explanation for this obser-
vation in a specific period of time was the systematic
prophylaxis with fluconazole in risk groups to develop
candidemia.
105
Similarly, a Cancer Center of Texas,
USA, and a tertiary health care center localized in
Haryana, India reported that 8% and 9% of candidemia
cases were associated with C. krusei, respectively, but in
these cases, the studies were conducted in a pediatric
population.
106,107
Another study from the USA, but in
this case performed in Ihowa, reported that 3.4% of can-
didemia cases were due to infection with C. krusei, and
these showed the lowest 90-day survival rate.
108
A study
that enrolled 26 short-stay university hospitals in the Paris
area reported that the candidemia incidence caused by
C. krusei in patients not admitted to ICU was 5.2% in
patients with hematological diseases, 3.7% in patients with
an oncological condition, and 1.2% in patients with no
malignancy diagnosed; while in patients in ICU, the fig-
ures were 5.1%, 4.4%, and 2.3% for patients with
a hematological disease, oncological conditions, and no
malignancy, respectively.
109
Similarly, studies conducted
in the Republic of Korea, Australia, Spain, the USA, India,
Taiwan, Saudi Arabia, and Portugal reported that 2.6%,
4%, 6%, 5%. 3.3%, 4%, 6%, and 5% of candidemia cases
were caused by C. krusei, respectively, with 25% of the
Portuguese isolates resistant to posaconazole.
110–118
Contrary to these figures though, a study based on
a tertiary care hospital in North China found that only
0.9% of the candidemia cases were caused by
C. krusei.
110–118
Similar to this Chinese study, reports
from two Greek, one Brazilian, one Swiss consortium of
hospitals, and one Mexican tertiary hospital found that
1.8%, 0.2%, 1%, 2%, and 2.2% of candidemia cases
were caused by C. krusei, respectively,
119–123
and a study
conducted in neonates admitted to ICU, participating in
the National Nosocomial Infection Surveillance system
from 1995 to 2004 in the USA reported only 0.15% of
candidemia cases associated to C. krusei.
124
As an outlier report, a study carried out in the
University of Texas M. D. Anderson Cancer Center with
clinical records of patients admitted from 1993 to 2003
found that C. krusei was the causative agent of 24% and
2% candidemia cases in patients with hematological
malignancies and solid tumors, respectively.
125
The
authors of this study proposed that this prevalence in
patients with hematological conditions is due to the pre-
valent use of fluconazole as a prophylactic antifungal
agent, especially in patients with hematological malignan-
cies and recipients of bone marrow transplantation.
125
The
figures above reported were similar in the period of 2001
to 2007 in the same cancer center, where 17% of candide-
mia cases were caused by C. krusei.
126
The risk factors for fungemia due to C. krusei include
the recent surgery report (< 30 days), artificial implants,
splenectomy, neutropenia, the presence of oncological
conditions such as solid tumors, acute leukemia, or lym-
phoma as an underlying disease; stem cell transplantation,
preexposure to fluconazole, echinocandins or antibacterial
agents, specifically vancomycin or piperacillin-
tazobactam.
104,109,110,125,127,128
At first glance, it is diffi-
cult to relate the use of antibacterial agents with the risk to
acquire an infection caused by C. krusei or other Candida
species. It has been proposed that vancomycin can alter the
ecology of the normal skin microbiota, promoting coloni-
zation by Candida species and thus increasing the poten-
tial to develop a systemic infection; while anti-anaerobic
antibacterial agents such piperacillin-tazobactam, may pro-
mote overpopulation of yeast species and colonization of
the gastrointestinal tract.
128
In neonatal patients, among
the risk factors associated with C. krusei fungemia are
parenteral nutrition, recent fluconazole exposure, use of
broad-spectrum antimicrobials, and the presence of
a percutaneous inserted central catheter.
129,130
Besides the systemic disease, C. krusei is also asso-
ciated with superficial infections. This organism can cause
bronchopneumonia and vulvovaginal candidiasis but is
a rare etiological agent in the latter, being isolated only
in 0.1% of cases and has a good response to nystatin.
131,132
C. krusei has been also found infecting the tonsils, where
only surgical removal of the organ offered a permanent
cure, causing septic arthritis, ulcers, urinary tract infec-
tions, and vasculitis
133–136
In veterinary, this organism can also cause infections
and deteriorate the health conditions in animals. C. krusei
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was reported as the causative agent of bovine bronchop-
neumonia and mastitis in Japan, China, Turkey, Algeria,
Canada, Polony, and the United Kingdon;
137–143
while in
cats could be responsible for the failure of long-term
gastrostomy tubes.
144
For the case of bovine mastitis, it
has been suggested that wheat silage, rather than unappro-
priated milking is the source of the C. krusei cells affecting
the udder.
145
Despite it is part of the normal microbiota of
birds, C. krusei has been associated with gastrointestinal
diseases in white-crowned parrots (Pionus senilis),
146
and
acute necrotizing ventriculitis in Eclectus parrot (Eclectus
roratus).
147
C. krusei Identification
Since C. krusei belongs to a fungal genus that contributes
with several species as etiological agents of candidiasis,
the methods for identification of C. krusei have been
originally developed to discriminate C. albicans from
other species. Nonetheless, the following strategies have
been refined to identify other Candida species, including
C. krusei.
Biochemical reactions are the most common strategies
for speciation of Candida isolates, and these have been
taken into account to develop chromogenic media that
easily differentiate Candida species, depending on the
color and morphology of the colonies growing on the
plates. C. krusei generates purple fuzzy, large rough colo-
nies with flat pale edges when grown on HiCrome
Candida; while the color change to pink fuzzy when cul-
tured on CHROMagar Candida (CHROMagar) or
CHROMagar-Pal’s plates.
148
In Brilliance™Candida
Agar (formerly Oxoid Chromogenic Candida Agar,
OCCA) this species grows like dry, irregular pink-brown
colonies.
149
Even though this colony color could be infor-
mative for species identification, it could be mistaken with
the one generated by other species that develop pinkish
colonies, such as C. parapsilosis, Candida kefyr, and
Candida haemulonii.
148,149
Another medium for quick
detection of Candida species is CandiSelect™4
(BioRad), where C. krusei generates large turquoise-blue
colonies with a characteristically rough morphotype, a dry
appearance, and an irregular outline. However,
C. tropicalis and C. glabrata also grow like smooth, tur-
quoise colonies, making the species identification
troublesome.
150
Due to these limitations, these media are
used for preliminary species identification, and additional
phenotypic or genotypic tests should be included for the
proper identification of C. krusei and other Candida
species. The API ID32C method is currently the gold
standard for phenotypic characterization of these organ-
isms, but another alternative is Micronaut-Candida
(Bornheim), a microplate-based system that contains 21
biochemical reactions, and 14 carbohydrate assimilation
tests (melibiose, D-xylose, L-rhamnose, gentibiose,
D-glucose, inositol, cellobiose, saccharose, trehalose,
galactose, maltose, lactose, raffinose, and a control reac-
tion), and urease test with its control. Results are generated
in 24 h and interpretation assisted by the Micronaut
software.
151
This strategy proved to be as good as the
API ID32C method for the C. krusei identification.
151
The Vitek 2 system (bioMérieux) is an automated alter-
native for C. krusei identification based also on biochem-
ical reactions and has 100% specificity to identify this
species.
152
Another alternative for Candida identification based on
phenotypic traits is the analysis of volatiles using offline
gas chromatography and mass spectrometry. The p-xylene,
2-octanone, 2-heptanone, and n-butyl acetate are signature
volatiles of the C. krusei presence in in vitro analyses.
153
Among the molecular strategies, PCR is one of the
techniques thoroughly analyzed and applied for the identi-
fication of C. krusei and other Candida species. It was
reported that a single primer pair aiming to amplify
a fragment of L1A1 gene, which encodes for
a cytochrome P-450 lanosterol-14α-demethylase, was cap-
able of detecting fungal DNA in clinical specimens with
a sensitivity of 200 fg of DNA but the amplicon size was
not useful for Candida species discrimination, as this was
in the range of 336 to 350 bp for all the analyzed
species.
154
However, combined with restriction enzyme
analysis using HincII, NsiI, and Sau3A it was generated
a species-specific pattern of restriction fragments.
154
Similarly, the amplification of the gene coding for the
small ribosomal subunit 18S-rRNA and restriction with
AluI, BanI, BbsI, DraII, Eco147I, and NheI generated
a species-specific profile able to discriminate C. krusei
from other Candida species.
155
The PCR-RFLP method
amplifying the ITS1-5.8S-ITS2 rDNA region followed by
restriction with MspI was reported as another alternative to
identify this organism.
156
Alternatively, a PCR method using a primer pair that
amplifies the polymorphic species-specific repetitive
sequence C. krusei repeated sequence 1 (CKRS-1) of the
non-transcribed intergenic regions of rRNA genes showed
100% specificity and a sensitivity to detect 10 to 100 fg of
purified DNA.
157
Another alternative for C. krusei
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identification by PCR is the amplification of part of the
gene encoding for topoisomerase II. A nested PCR reac-
tion using a combination of degenerate and specific pri-
mers was reported to amplify a characteristic 227 bp DNA
fragment from the C. krusei genome, with 100% specifi-
city and a sensitivity of 40 fg of genomic DNA.
158
The real-time PCR has been also adapted for C. krusei
identification. The amplification of the 5.8 rRNA gene
demonstrated that was possible to obtain positive reactions
with a detection limit of 10 CFU/mL blood, with 100%
specificity.
159
More recently, it has been developed the CanTub-simplex
PCR based on the amplification of the gene encoding for
β-tubulin in a real-time platform, where the amplicons melt-
ing temperature is species-specific.
160
Following the same
rationale, amplification of the internally transcribed spacer
region 2 and analysis of melting peaks and curves, allowed
the discrimination of C. krusei from the other 15 Candida
species included in the study.
161
The current molecular alternatives developed for C. krusei
identification also include microarrays. Based on the nucleo-
tide sequences of the internal transcribed spacer regions (ITS1
andITS2)oftherRNAgeneachiptoidentify32fungal
pathogens was recently reported.
162
Even though the results
of the microarray and the automated system Vitek 2 were
concordant in 96.7% of cases for all the pathogens tested, for
the case of C. krusei the specificity was of 100%.
162
The multianalyte profiling system has also been adapted
for the identification of Candida species. This consists of
mixed polystyrene beads covalently linked to specificDNA
probes for C. albicans, C. glabrata, C. tropicalis,
C. parapsilosis, C. krusei,andC. dubliniensis, which are
incubated with amplicons containing the ITS2 region of
Candida species rRNA gene previously amplified with uni-
versal fungal primers. The beads conjugated with the corre-
sponding amplicons are analyzed in the multianalyte
profiling system flow cytometer that measures the fluores-
cence produced by the different pairs of amplicons and
beads.
163
This approach was 100% specificandshowed
a sensitivity limit of 0.5 pg of DNA.
163
The strategies for C. krusei identification also include
immunological tests, although these are not as specificas
the molecular methods. The Krusei color test (Fumouze) is
a latex beads agglutination assay performed with red par-
ticles coated with a monoclonal antibody that specifically
reacts with a C. krusei antigen found on the cell surface.
Although all the C. krusei strains used in the study agglu-
tinated the latex beads, false-positive reactions were
observed with C. famata, C. glabrata, C. guilliermondii,
C. kefyr, C. parapsilosis, and C. tropicalis.
164
Therapy
The treatment of Candida infections includes the use of sev-
eral kinds of family compounds, named polyenes, azoles,
echinocandins, nucleoside analogs, and allylamines.
Fluconazole is one of the most common antifungal drugs
used for empirical treatment of candidiasis; however,
C. krusei is a species intrinsically resistant to this drug, with
more than 95% of clinical and veterinary isolates being fluco-
nazole-resistant.
141,165
The mechanisms behind this observa-
tion are not fully understood yet, but the flux pump activity of
the ATP-binding cassette transporter Abc1 and reduced fluco-
nazole affinity to Erg11 have been associated with this pheno-
typic trait.
165,166
It has been also proposed that both proteins
could be part of the resistance mechanisms observed in some
itraconazole-resistant strains.
165
The in vitro acquisition of
resistance to voriconazole has been reported after exposing
daily C. krusei to 1 µg/mL of the drug. In these cells, drug
resistance was associated with increased expression of the
ABC1 gene and point mutations within ERG11.
167
Several studies conducted with clinical samples have
shown that most of the C. krusei strains are susceptible to
voriconazole, itraconazole, posaconazole, anidulafungin,
micafungin, 5-flucytosine, and amphotericin B; but inter-
mediate resistance to caspofungin has been reported in
some isolates.
168–170
Although C. krusei is a rare etiological
agent of vaginitis, the use of local clotrimazole, ciclopirox
olamine, terconazole, and boric acid is recommended.
171,172
In veterinary infections though, isolates resistant to fluor-
ocytosine, itraconazole, ketoconazole, and amphotericin
B have been reported.
141
The pharmacological alternatives
to treat candidiasis caused by C. krusei in animals include
sulphamethoxypyridazine in cases of bovine mastitis.
173
There is a vast amount of studies addressing the search
and design of compounds with antifungal activity, as well
as the use of herbal derivatives with anti-Candida activity,
with the potential of being explored as new alternatives to
control candidiasis. Among the most relevant new alter-
natives are VT-1161 and VT-1129, a new generation of
CYP51 inhibitors, a lanosterol 14-α-demethylase that
belongs to the cytochrome P450 family and has a role in
ergosterol biosynthesis, which showed the inhibition of
C. krusei growth at concentrations of ≤2μg/mL after
24 h of incubation.
174
Another alternative that is currently
under investigation is the use of nanoparticles to deliver
antifungal drugs into the fungal cells. It has been recently
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demonstrated that lipid core nanocapsules containing flu-
conazole were capable of reducing the effective dose of
this antifungal drug and reverted the resistance to flucona-
zole observed in several C. krusei strains.
175
The use of
palmatine, in combination with either fluconazole or
itraconazole, has shown antifungal synergism, in
a mechanism that inhibits the efflux pumps, with the con-
sequent increment in the intracellular azole content.
176
A trypsin inhibitor from Tecoma stans (yellow elder)
leaves has been isolated, characterized, and shown to have
anti-Candida activity.
177
The minimal inhibitory concentra-
tion for this compound against C. krusei cells was 100 µg/
mL, whereas the minimal fungicidal concentration was 200
µg/mL. ATP depletion and lipid peroxidation are thought to
be the mechanisms behind its antifungal activity. In addition,
it showed no cytotoxicity against human PBMCs,
177
being
a promising candidate to move forward in the search for new
antifungal compounds to treat candidiasis. Flavonoid and
tannic fractions from Psidium guajava L. contain high levels
of phenolic compounds and showed anti-C. krusei activity
that synergizes with fluconazole and affects the morphologi-
cal transition.
178
Similarly, flavonoids from Plinia cauliflora
leaves, which mainly contain glycosylated quercetin and
myricetin showed inhibitory activity against C. krusei (mini-
mal inhibitory concentration of 19 µg/mL) and low cytotoxi-
city effect on human cells.
179
The water-insoluble fraction
from Uncaria tomentosa (cat’s claw) showed a synergistic
effect with either terbinafine or fluconazole in a mechanism
that involves the action of the plant proanthocyanidins on the
fungal cell wall.
180
These studies show that traditional medicine, mainly
based on herbology, could be a source of a new generation
of antifungal drugs.
Animals are also a source of molecules with antifungal
activity. The 2-lysophosphatidylcholines isolated from deer
antler extracts showed fungistatic activity, suppressing the
morphological transition in C. albicans, C. krusei,
C. guilliermondii,andC. parapsilosis,inamechanism
mediated through the mitogen-activated protein kinase
pathway.
181
Concluding Remarks
In recent years, there is a significant amount of information
gathered about C. krusei biological and clinical aspects, under-
scoring the relevance of this organism as an emergent species,
most likely because of its intrinsic resistance to fluconazole.
The C. krusei genomic sequencing has opened new doors for
basic research in this organism that could be translated into
clinical applications. The genes prediction, along with their
organization within the genome, the proteomic, transcrip-
tomic, and metabolomic analyses could unveil species-
specific genes related to virulence or drug resistance,
information that could be later exploited in the diagnosis or
treatment of the infection. The isolation of this organism from
vegetal material and animal dropping points out to the envir-
onment as the source of candidiasis caused by C. krusei and
provides the background to expand this kind of analysis to get
a closer panorama of the C. krusei ecological distribution. The
further expansion of our current knowledge on the C. krusei-
host interaction would discover singularities in this species,
which might be exploited for the design of alternative strate-
gies to control the disease caused by this and other Candida
species. This is of particular interest because thus far no
vaccine is currently available to prevent candidiasis.
182
However, new immunotherapeutic approaches, and the ulti-
mate development of a vaccine against Candida species will
rely on the deep knowledge of the immunity against these
organisms.
Even though there are phenotypical and molecular strate-
gies to identify C. krusei available in the clinical setting,
faster, cheaper and more accurate alternatives are desirable
for the early diagnosis of C. krusei and other Candida species.
We provided some examples of natural products that could
have antifungal activity, and these efforts should be replicated
and look into the mechanisms behind the antifungal effect, as
these compounds could be part of a new generation of drugs
to treat candidiasis and other fungal infections. Finally, the
search for the mechanisms behind the resistance to flucona-
zole in this species would provide useful information for the
design of new treatment alternatives.
Acknowledgments
This work was supported by Consejo Nacional de Ciencia
y Tecnología (ref. PDCPN2014-247109, and FC 2015-02-
834), Universidad de Guanajuato (ref. CIIC 087/2019), and
Red Temática Glicociencia en Salud (CONACYT-México).
Disclosure
The authors declare no conflicts of interest in this work.
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