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Cell biology of Candida albicans–host interactions

Alessandra da Silva Dantas1, Kathy K Lee1, Ingrida Raziunaite1,
Katja Schaefer1, Jeanette Wagener1, Bhawna Yadav1 and
Neil AR Gow

Candida albicans is a commensal coloniser of most people and exploring the interface between commensalism and path-
a pathogen of the immunocompromised or patients in which ogenesis.
barriers that prevent dissemination have been disrupted. Both
the commensal and pathogenic states involve regulation and
adaptation to the host microenvironment. The pathogenic Life as a successful saprophyte
potential can be downregulated to sustain commensalism or C. albicans is a largely asexual fungus, but never-the-less it
upregulated to damage host tissue and avoid and subvert is morphologically and physiologically a highly variable
immune surveillance. In either case it seems as though the cell and adaptable fungus. It is pleomorphic — being able to
biology of this fungus has evolved to enable the establishment grow either as a budding yeast, or as a pseudomycelium of
of different types of relationships with the human host. Here we elongated and conjoined yeast cells or as true hyphae
summarise latest advances in the analysis of mechanisms that formed of generate parallel-sided tip-growing filaments
enable C. albicans to occupy different body sites whilst [5]. It also exhibits a non-sexual form of variation called
avoiding being eliminated by the sentinel activities of the phenotypic switching that can generate stable cell and
human immune system. colony variants with distinct properties [6]. C. albicans can
thrive in different host niches (gut, vagina, oral mucosa,
Address skin) without causing disease. This observation suggests
The Aberdeen Fungal Group, School of Medicine, Medical Science and
Nutrition, Institute of Medical Sciences, University of Aberdeen,
it is adapted for commensalism. GI tract colonization
Aberdeen AB252ZD, UK seems to involve predominantly carriage of the yeast form
of the fungus, and low level systemic dissemination in the
Corresponding author: Gow, Neil AR (n.gow@abdn.ac.uk) gut can occur even in yeast-locked mutants [7]. However,
1
These authors contributed equally and are listed alphabetically.
a mouse model of stable gastrointestinal candidiasis dem-
onstrated that passage of C. albicans through the mamma-
Current Opinion in Microbiology 2016, 34:111–118
lian gut leads to the transition to a modified yeast cell,
This review comes from a themed issue on Parasitic and fungal
‘GUT phenotype’ (gastrointestinally induced transition),
diseases
that expresses a specialised transcriptome in the digestive
Edited by Gero Steinberg tract to promote assimilation of common nutrients in the
For a complete overview see the Issue and the Editorial bowel. These GUT cells are morphologically altered and
Available online 28th September 2016 suppress the propensity for tissue invasion and the ex-
http://dx.doi.org/10.1016/j.mib.2016.08.006 pression of certain virulence traits [8]. Therefore, the
commensal state does not solely depend on host immune
1369-5274/# 2016 The Authors. Published by Elsevier Ltd. This is an
open access article under the CC BY-NC-ND license (http://creative-
status and is also supported by organism-specific adapta-
commons.org/licenses/by-nc-nd/4.0/). tions mediated by transcriptional changes in the host-
associated commensal state [9].

Changes in the availability of nutrients in the gut due to

dietary intake, can further impact the abundance of
Candida [10], and changes in diet or gut fungal microbiota
Introduction may lead to dysbiosis and inflammatory pathologies such
Candida albicans is the commonest serious fungal patho- as Crohn’s disease [11,12]. Although Candida colonisation
gen of humans, variously reported as causing between may promote gut inflammation under certain circum-
250 000 and 400 000 deaths per annum worldwide as well stances, chitin, a component of the Candida cell wall,
as extensive morbidity of around 100 million episodes has anti-inflammatory properties and has the potential to
of recurrent vaginitis [1,2]. This fungus is a classical ameliorate inflammatory bowel disease (IBD) if exposed
opportunistic pathogen residing harmlessly as a commen- in the gut [13]. Also host mutations in, for example, fungal
sal in approximately 50% of individuals [1], kept in check immune recognition receptors such as dectin-1, the im-
by our immune system and a protective bacterial micro- mune signalling molecule CARD9 and the inflammatory
biome of the gut and other mucosal surfaces [2–4]. In cytokine IL-22 result in susceptibility to colitis and other
this review we survey latest advances in the cell biology of forms of IBD [14,15]. In a mouse model, tryptophan
C. albicans that underpins its ecology as an organism metabolites from some specific members of the gut

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112 Parasitic and fungal diseases

microbiome were shown to be able to suppress C. albicans cleavage of host immune defence proteins, and thus aid
colonisation by controlling secretion of IL-22 in stomach nutrition acquisition, invasion and evasion of the patho-
[16]. Probiotic supplements are also known to suppress gen from host immune defence [30,31]. These hydrolases
the fungal mycobiome [17]. Therefore the commensal belong to multigene families, and each family member
status of Candida is also related to the host microbiome as has a different substrate specificity, pH optimum, and
a whole and the immune status of the host. expression profile [30]. Of these the secreted aspartyl
proteases (Saps) have been shown to have important
Collectively, these observations suggest that gut com- multiple roles. Regulation of the expression of this 10-
mensalism of Candida is related to both intrinsic factors membered gene family is regulated principally by host
(fungal gene regulation, cell morphology, adaptation, carbon and nitrogen sources and by pH [32]. Sap2 inacti-
fungal burden) and extrinsic factors (competitive micro- vates Factor-H and the complement receptors CR3 and
biome, diet, host immune status). We know less about the CR4 on macrophages, thus mediating the escape of
factors affecting colonisation at other body sites although C. albicans from recognition by the host’s innate immune
it is likely that a similar complex array of factors sustain system [33]. In mice, Anti-Sap2 antibodies or the protease
the commensal state in these host niches. inhibitor pepstatin A can reduce Sap2-mediated vaginal
inflammation caused by C. albicans [34]. Sap2 and Sap6
Life as a successful pathogen have also been shown to induce inflammatory cytokine
During the course of infection C. albicans colonizes vari- production by the host through the type I IFN, and
ous host niches, with differences, for example, in nutrient caspase-11 induction as well as NLRP3 inflammasome
availability, pH, hypoxia and CO2 levels [18,19]. One of activation [35,36]. Following their uptake by the host
the key features establishing C. albicans as a successful epithelial cells, hypha-specific Saps4-6 cause lysosomal
pathogen is its adaptability to successfully thrive in these permeabilization and triggering of caspase-1 dependent
different conditions [18]. Host microenvironments have apoptosis [37].
heterogeneous carbon sources and, as it traverses through
different host niches, C. albicans can adapt to use alterna- Recently, an entirely novel secretory host cell lysing
tive carbon sources simultaneously, for its survival and agent from C. albicans, called ‘candidalysin’, has been
virulence [18–20]. This adaptation has resulted from the described. The lytic activity is encoded by one of eight
absence of catabolite inactivation due to the rewiring of Kexp-processed peptides from the ECE1 gene product.
ubiquitination sites in metabolic enzymes [21,22]. The The Ece1-III62–93 peptide alone can induce damage to
metabolic flexibility of Candida also contributes to the epithelial membranes and the activation of a danger
alterations in the cellular proteome and secretome [23], response in host epithelial immunity [38].
and its ability to undergo yeast to hyphal transition, white-
opaque switching [24], biofilm formation, as well as its These evolutionary adaptive traits enable C. albicans to
adhesion characteristics [23,25], and the capacity for cell survive in various host niches, counter host immune
wall remodelling [19,20,23,26]. Changes in cell wall poly- defences and help C. albicans in establishing itself as a
saccharide composition [19,20,25], modifies the patho- successful pathogen (Figure 1).
gen’s sensitivity to environmental stress and antifungals
[18,20,23,25], but also affect its immunogenicity by alter- Controlling interactions with human epithelia
ing the expression and presentation of critical pathogen- and endothelia
associated molecular patterns (PAMPs), thus making Two complementary mechanisms are involved in
C. albicans a moving target for the recognition by the C. albicans host cell invasion through epithelial cells
host immune system [19,20,21,25–27]. (EC) (Figure 3). Fungal-induced endocytosis contributes
to the early stages of invasion, a process of host produced
The human host withholds the availability of micronu- pseudopods surrounding the fungus to pull it into the host
trients, like Fe, Zn, Cu and Mn, from the pathogen in a cell. By contrast, active penetration occurs at later time
process termed ‘nutritional immunity’ [28]. These micro- points when hyphae invade between or through ECs [39].
nutrients are essential for many vital cellular functions Although the mechanisms involved depend on invasion
in the pathogen [28]. Countering this, C. albicans has stage, fungal morphology and epithelial lineage, both are
evolved mechanisms to overcome host nutritional immu- triggered by hypha-associated factors [40]. Notably, sys-
nity by expressing micronutrient transporters (e.g. Rbt5/ temic dissemination, which is not dependent on morpho-
Als3 for Fe; Zrt1/Zrt2/soluble Pra1 for Zn) [28], or redun- logical transition, occurs from the GI tract and trans-
dant enzymes that use alternative micronutrients as cofac- epithelial transport of the yeast form might be mediated
tors [29]. by indirect mechanisms, such as by lumen sampling
dendritic cells or M cell transcytosis [7].
C. albicans expresses a number of proteases, phospholi-
pases, lipases and esterases (reviewed in [30]), which Both the oral and vaginal epithelial immune response
function in the degradation of host connective tissues, differs to the presence of hyphae and yeast cells of

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 Candida–host biology da Silva Dantas et al. 113

Figure 1

Metabolic Flexibility:
Hydrolytic Enzymes
Efficient use of alternate
Saps, Lip, Plp:
carbon sources,
Degradation of host
stress resistance, cell connective tissues,
Evasion from host surface changes cleavage of host immune
immune system:
factors,
Changes in cell wall nutrient acquisition
architecture and
composition, masking
of PAMPs Candidalysin:
Secretory cytolytic
Escape from peptide damaging
phagocytosis: host immune cells
Vomitosis,
hyphal lysis of host cells, Key Virulence
phagolysosomal
neutralization, Factors of
pyroptosis
Candida Phenotypic Switching:
Opaque cells resistant
to neutrophil
Countering Host
Nutritional Immunity:
albicans engulfment

Micronutrient uptake
transporters and
redundant proteins with
alternate cofactors Biofilm formation:
Resistant to
Yeast to Hyphal
antifungals and host
Morphogenesis:
immune defence
In response to
temperature, serum, Adherence to Host
alkaline pH, nutrient Surfaces:
starvation, CO2 Expression of
adhesins

Current Opinion in Microbiology

Candida virulence factors. Virulence is a polygenic trait in C. albicans involving biochemical, physiological, genetic and morphogenetic
characteristics.

C. albicans so that only large numbers of hyphae activate a of invasion itself [43]. These include the expression of the
host biphasic MKP1 and c-Fos dependent response lead- GPI-linked cell surface proteins Hwp1 and the invasin
ing to inflammatory cytokine formation [41]. This may Als3 or Ssa1, a member of HSP70 family [40]. Hwp1,
allow the epithelium to control the pattern of immune under control of the transcription factor Bcr1 regulating
activation so it is responsive mainly to fungal invasion biofilm formation, acts as a substrate for epithelial trans-
rather than colonisation. Low level colonisation, may glutaminases and is required for mucosal pathogenicity
progress to the establishment of a mature surface biofilm, [39]. Als3 and Ssa1 mediate binding to host epithelial
but as yet it is not clear how the establishment of a surface receptors which enable the fungus to attach to and
Candida biofilm may affect mucosal infection and immu- invade host cells. Host ligands include E-cadherin on
nity [42]. However, it would seem likely that mature ECs, N-cadherin on endothelial cells and EGF receptor
biofilms would present challenges for the cellular im- on oral ECs [40]. During induced endocytosis this inter-
mune system to clear such dense biomass mats. action stimulates host cytoplasmic proteins to form cla-
thrin-coated vesicles surrounding the fungus for an actin
Multiple stimuli including EC contact and body temper- dependent internalization. E-cadherin interaction is how-
ature trigger hyphal morphogenesis. C. albicans produces ever not necessary for endocytosis of C. albicans into
early virulence factors that are downstream of the process enterocytes [44]. Recently it has been shown that

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114 Parasitic and fungal diseases

Figure 2

migration

killing

recognition
non-lytic
expulsion

phagosome
maturation
engulfment

escape pyroptosis

Current Opinion in Microbiology

Interaction of C. albicans with macrophages showing the stages at which the fungus can deploy immune avoidance mechanisms. The
macrophage uses chemotaxis to target the fungal cell, then fungus recognition and engulfment take place via interaction of fungal PAMPs and a
series of immune cell PRRs that includes phagocytic receptors. The Candida cell is delivered to the phagosomal vesicle which undergoes fusion
with lysosomes to create the mature acidic phagolysosome that can kill the fungal cargo using oxidative and nitrosative elements. However, C.
albicans has the capacity to interfere with the phagolysomal maturation programme, increase its alkalinity, generate protective antioxidants and
induce its own non-lytic expulsion. In addition, hypha formation and induced pyroptosis can cause the lysis of the phagocyte.

C. albicans Als adhesins are also involved in adhesion to receptors (PRRs). These recognition events are dominat-
C. glabrata during oropharyngeal candidiasis (OPC) en- ed by binding of fungal cell wall carbohydrates, although
abling C. glabrata to colonize and persist in the oral the cell wall proteins also contribute to shaping the
mucosa and cavity [45]. immune response [3,4]. Recently it has become clear that
the innate immune response, which is of principle impor-
During active penetration, C. albicans secretes hydrolytic tance in conferring immunity, can be trained by prior
enzymes (described in previous section) that affect epi- exposure to Candida. As a consequence memory of prior
thelial cell–cell junctions and facilitate degradation of cell innate immune interactions is epigenetically imprinted in
membrane components along with other ligands that the host and results in enhanced immune responses in
facilitate fungal adhesion [39]. Cell surface localized subsequent encounters with the fungus. The paradigm of
superoxide dismutase detoxifies reactive oxygen species immunological memory was thought previously to be
(ROS) produced when tissue is damaged and is also encoded entirely by the adaptive immune system but is
expressed on the surface of invading hyphae [46,47]. clearly also a feature of innate immunity [48,49].

Many other internal and cell wall-associated proteins also It is also increasingly evident that the immune response
indirectly affect C. albicans adhesion and virulence, for to Candida is influenced by yeast-hypha morphogenesis
example, proteins involved in protein trafficking and [50]. Hyphae specifically activate the NLRP3 inflamma-
required for a functional vesicle transport system or some resulting in IL-1b secretion [51] and yeast and
proteins involved in hyphal formation, growth or cellular hyphae are differentially bound to, taken up and pro-
orientation. Others have a crucial role in cell wall assem- cessed by phagocytes [3]. In addition, other morphologi-
bly and integrity, or they modify other adhesins required cal transitions, such as the switching from the white to the
for epithelial binding [39]. opaque form of this organism results in differential phago-
cytosis and the suppression of the production of phago-
Interactions with phagocytes cyte chemoattractants [52,53].
Almost every component of the cell wall of Candida has
been shown to have a role in the interactions between host Resisting phagocytes
and pathogen. Immune recognition of Candida is mediated Following internalisation of the fungal target cell, matura-
by PAMP engagement with host pattern recognition tion of the phagosome into phagolysosome is fundamental

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 Candida–host biology da Silva Dantas et al. 115

Figure 3 harmful environment of the phagolysosome, C. albicans has

developed strategies to allow its survival by the manipula-
tion and escape from phagocytic cells (Figures 2 and 3)
(a)
[54,59].

C. albicans promotes neutralization of the phagolysosome,

in a process that requires the Stp2 transcription factor
induction of the Ato5-mediated ammonia exporter
[55,56]. The subsequent neutralization of the acidic en-
vironment of the phagolysosome allows C. albicans hyphal
morphogenesis to occur hence facilitating its escape from
macrophages [55,56]. In addition, the PKC-Mkc1-Rlm1
cell wall salvage pathway is also activated resulting in
reinforcing chitin being made in the cell wall [57,58].
(b)

When inside the phagosome Candida also induces a

battery of protective enzymes and proteins including
catalase, superoxide dismutase, thioredoxin, flavo-hae-
moglobin, glutathione recycling enzymes that degrade
or scavenge RNS and ROS [47,60]. Consequently, dele-
tion of key regulators of oxidative and nitrosative stress
response results in increased sensitivity to phagocyte
killing [47,60]. Multiple individual imposed toxic stresses
have been shown to exert synergistic effects on the ability
to kill Candida. These studies illustrate the importance of
20 µm the Hog1 MAPK and the Cap1 transcription factor in the
regulation of combinatorial stress responses [60,61].
(c)
Candida cells share a property with Cryptococcus and other
fungi to be able to induce their own non-lytic expulsion
from macrophages (sometimes called vomocytosis), with-
out any damage to the phagocyte [62]. By contrast,
numerous studies have reported the ability of elongating
hyphae to pierce the membrane of a macrophage result-
ing in their release [3]. However, there is no clear relation
between yeast-hypha morphogenesis and macrophage
lysis.

It is now clear that Candida hyphal cells can also induce

pyroptosis in the host phagocyte — a form of pro-
grammed cell death that is dependent on caspase-1
Current Opinion in Microbiology
activation of the NLRP3 inflammasome [63–66]. Howev-
er, although hyphae promote pyroptosis, pyroptosis is not
C. albicans interaction with host cells. [a] I invasion into oral
epithelium with hyphae that have penetrated the host cells marked (*).
always coincident with hypha formation. For example, a
[b] Phagocytosis by mouse peritoneal macrophages with extracellular vps35 mutant formed hyphae normally but failed to
parts of C. albicans stained with an anti-Candida Ab in green and induce macrophage lysis whilst, alg1 and alg11 mutants
counterstained with CFW in blue. The macrophages are stained red are hypha-deficient yet induced macrophage lysis via
with phalloidin (F-actin) to visualize phagocytic uptake. [c] Human
pyroptosis [67].
peripheral blood mononuclear cells aggregated around yeast cells and
hyphae of C. albicans.
Therefore the cell biology of Candida is well adapted to
resist the killing potential of phagocytes thereby limiting
the effectiveness of some elements of the adaptive im-
to fungal killing. The importance of phagolysosomes in mune system.
promoting fungal killing is associated with the presence of
cationic peptides, hydrolytic enzymes, ROS and reactive Conclusion
nitrogen species (RNS); which are generated in a vacuole C. albicans has numerous cell biology attributes that
with an acidic pH [3,54]. Hence, in order to survive the enable it to exist commensally in the human body. These

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116 Parasitic and fungal diseases

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