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Candida albicans morphology: still in focus

Ilse D. Jacobsen & Bernhard Hube

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morphology: still in focus, Expert Review of Anti-infective Therapy, 15:4, 327-330, DOI:
10.1080/14787210.2017.1290524

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EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, 2017
VOL. 15, NO. 4, 327–330
http://dx.doi.org/10.1080/14787210.2017.1290524
EDITORIAL
Candida albicans morphology: still in focus
Ilse D. Jacobsena,c,d and Bernhard Hube b,c,d
a
Research Group Microbial Immunology, Hans Knöll Institute, Jena, Germany; bDepartment of Microbial Pathogenicity Mechanisms, Hans Knöll
Institute, Jena, Germany; cFriedrich Schiller University, Jena, Germany; dCenter for Sepsis Control and Care, Jena University Hospital, Jena, Germany
ARTICLE HISTORY Received 10 January 2017; Accepted 31 January 2017
KEYWORDS Candida albicans; dimorphism; hyphal formation; quorum sensing; inhibition; hyphal associated genes; hyphal extension; compound screening
The yeast-to-hyphal transition (dimorphism) of the most com-
mon human pathogenic yeast Candida albicans remains in the
focus of molecular and medical mycology [1–4]. Since our
review on ‘C. albicans dimorphisms as a therapeutic target’ in
2012 [5], over 100 studies and reviews focusing on the mor-
phology of this yeast have been published, dealing with the
multiple aspects of this crucial virulence attribute.
The studies include diverse topics such as large-scale func-
tional screening studies [6–8], interaction with bacteria and
their products, interaction with other fungi, new regulatory
factors, the role of the vacuole and trafficking, hyphal-
associated genes and their functions, hyphal tip and directed
growth, hyphal extension and branching, the role of hyphal
formation during interaction with macrophages, and finally,
large-scale compound screening to identify inhibitors and
characterization of selected inhibitors.
As one of the new emerging topics, clinically relevant
interactions of C. albicans with bacteria were investigated by
several groups with fungal morphology as a crucial element. In
most studies, bacteria were found to inhibit fungal filamenta-
tion, often by secreted compounds that are linked to bacterial
quorum sensing, virulence factors, or metabolism [9–12]. In
the case of Fusobacterium nucleatum, however, hyphal inhibi-
tion was contact dependent [13]. Interestingly, both probiotic
and facultative pathogenic bacteria were shown to negatively
affect hyphal formation [9,10,12–15]. It, therefore, appears
possible that the interaction with bacteria, rather than distinct
environmental conditions or transcriptional programs, is
responsible for the predominance of C. albicans yeast mor-
phology in the gastrointestinal tract. Depletion of bacteria by
antibiotics might alleviate bacteria-induced suppression of
filamentation and thereby contribute to the shift of
C. albicans from a commensal to pathogen. This would be a
significant new finding as it may explain at least in part what
triggers the shift to pathogenicity.
Not all Candida–bacterial interactions are antagonistic; syner-
gistic interactions have been described, for example, for strep-
tococci [16], favoring mixed biofilm formation, and
Staphylococcus aureus. For S. aureus, the role of C. albicans
hyphal formation in the interaction appears to be niche specific:
While filamentation is dispensable for enhanced virulence in
CONTACT Bernhard Hube bernhard.hube@hki-jena.de Department of Microbial Pathogenicity Mechanisms, Hans Knöll Institute, Jena, Germany; Friedrich
Schiller University, Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
© 2017 Informa UK Limited, trading as Taylor & Francis Group
peritoneal coinfection [17], S. aureus uses attachment to
C. albicans hyphae to invade across mucosal barriers and to
cause systemic infections [18]. Similarly, it has been shown that
C. albicans hyphae can pave the way for another pathogenic
nonfilamentous Candida species, C. glabrata [19]. However, it
should be noted that C. glabrata can be highly pathogenic for
man, even without a coinfection with C. albicans [20].
Although the regulation of the morphological transition is
already well investigated [1–4,21], multiple new regulatory
factors directly or indirectly involved in hyphal formation and
new insights into regulatory mechanisms have been reported.
For example, it has been shown that activation of Ras1, a key
regulator of morphogenesis, requires proteolysis, mitochondrial
activity, and the adenylate cyclase Cyr1 [22,23]. Furthermore,
signaling for hyphal formation is associated with cell cycle-
independent phospho-regulation of Fkh2 [24] and mediated
by septins [25]. A genetic approach to dissect hyphal develop-
ment identified a novel function for the transcription factor
Ace2 [26], and diminished expression of the protein kinase
Cak1 was shown to bypass filamentation [27]. A similar subtle
level of regulation was shown when Hog1 basal activity was
reduced [28]. A further link in the complex regulatory network
was the identification of a novel feedback circuit formed by the
known regulators Brg1 and Nrg1 form [29]. In addition, cera-
mide synthases [30] and regulation of actin organization [31]
play important roles during filamentous growth. A novel link
between phenotypic switching and yeast-to-hyphal transition
was also found by demonstrating that white and opaque cells
undergo distinct programs of filamentous growth [32]. These
studies nicely complete our understanding of the already com-
plex picture of the regulation of dimorphism.
Three further subtopics in regulation of hyphal develop-
ment were in the highlights: (1) the role of oxygen concentra-
tions, (2) the role of the mediator complex, and (3) quorum
sensing. Clearly, in vivo hyphal formation is mediated by a mix
of environmental signals in the host, which includes hypoxia,
temperature, CO2 concentrations, and nutrient conditions,
which in turn require a complex network of signaling factors
and modules [33,34]. An interesting connection between fila-
ment regulation and the general transcription machinery has
been found by the discovery that the mediator complex is
328 I. D. JACOBSEN AND B. HUBE
directly linked to transcriptional regulation of hyphal regula-
tors and hypha-associated genes [35–37]. Farnesol is the
dominant quorum-sensing molecule and acts via different
pathways. Novel discoveries of its mode of action include
inhibition of Cup9 degradation, which in turn leads to
repressed expression of SOK1, encoding a kinase required for
degradation of Nrg1 to facilitate initiation of hyphal growth
[38]. Farnesol-mediated cell death was found to depend on
Efg1 and Cph1, thereby possibly explaining the lower resis-
tance of opaque cells to farnesol [39]. A new discovery was
that farnesol affects not only hyphal initiation but also hypha-
to-yeast transition [40], which might partially explain the
hyphal maintenance defect of an EED1 deletion mutant. This
mutant is the first identified to be hypersensitive to farnesol,
via unknown mechanisms distinct from pathways known to be
targeted by farnesol, and at the same time produces increased
amounts of this molecule [41]. After over a decade of intensive
research on farnesol, many open questions remain regarding
the existence of receptors and transporters and regulation of
its synthesis, recently summarized in a commentary by
Nickerson and Atkins [42]. Finally, recent evidence demon-
strates that it negatively affects the host immune response
[43,44], thereby reducing its suitability for therapeutic
approaches.
In contrast to the well-characterized hyphal initiation, the
mechanisms of hyphal extension are poorly understood but are
in the focus of more recent studies [1]. One of the critical factors
for hyphal extension is Eed1, a regulator of Ume6. As mentioned
above, Eed1 controls farnesol sensitivity, and farnesol resistance
might contribute to hyphal maintenance [41]. The molecular
mechanisms behind this are still elusive. An interesting finding
was that phosphorylation of Exo84 by Cdk1–Hgc1 is necessary
for efficient hyphal extension [45]. As part of the exocyst, this
complex is essential for cell surface expansion. In Saccharomyces
cerevisiae, phosphorylation of Exo84 leads to exocyst disassem-
bly, demonstrating redirection of conserved pathways in
C. albicans to facilitate hyphal maintenance. Clearly, the main-
tenance of hyphal extension is as important as the initiation of
hyphal formation and should be further investigated in detail.
Similarly, we still know very little about the hyphal-to-yeast
transition, which is equally crucial for pathogenicity and com-
mensal growth.
Critical for the pathogenic potential of hyphae is also the
directed growth and extension at the hyphal tip. This requires,
among others, the protein Cdc42 [46,47]. The dynamics of this
GTPase and the local activity [48] control directional growth
and promote thigmotropism, which contributes to invasion.
Hyphal tip growth requires intracellular compartments, vesicles,
and trafficking. For example, it has been shown that prevacuo-
lar compartment RabGTPases impact hyphal growth [49]; that
the protein Sec2p is physically associated with SEC2 mRNA on
secretory vesicles [45]; and that vacuolar acidification is essen-
tial for morphology and virulence [50]. One new, but related,
aspect of hyphal growth and pathogenicity is hyphal branching,
which precise role still remains to be elucidated [51,52].
Of note, the virulence potential of hyphae is not mediated
by the hyphal morphology per se, but by genes which expres-
sion is associated with the morphological program. For
example, the hyphal wall protein 1 (Hwp1) is required for
virulence in distinct niches [53] and Csa2, a member of the
Rbt5 protein family, is involved in the utilization of iron from
hemoglobin during hyphal growth [54]. However, one study
showed that hyphal growth does not always require induction
of hyphal-specific genes [55], and another study found that
the core filamentation response network is restricted to only
eight genes [56].
One of these genes, ECE1, was already discovered in the
1990s due to its high expression during hypha formation.
However, its function remained unknown until last year [57].
In fact, Ece1 is a polyprotein consisting of eight short peptides,
each separated by lysine–arginine residues. The polyprotein is
sequentially processed at these dibasic amino acids by two
serine proteases, resulting in peptide secretion. One of these
peptides adopts an α-helical structure and permeabilizes host
epithelial membranes causing cell lysis and was therefore
named Candidalysin. Deletion of the Candidalysin-encoding
region from the ECE1 gene abolished the ability of
C. albicans to damage epithelial cells and significantly attenu-
ated virulence. Therefore, the production of Candidalysin
rather than hyphal formation per se is the mediator of host
(epithelial) cell damage. These observations provide the elu-
sive link between hyphal formation and host (epithelial) cell
damage and explain why C. albicans filaments are the patho-
genic morphology during mucosal infections.
Hyphal formation also plays a key role during interaction
of C. albicans with macrophages. Here, significant progress
has been made in elucidating some vital questions: How
does C. albicans inhibit phagosome acidification? Which
intracellular mechanisms cause hyphal formation? How is
hyphal formation linked to host cell death? One study
showed that hyphal formation and masking of β-glucan via
mannan inhibit macrophage phagosome maturation and
thus acidification [58]. However, active alkalinization of the
phagosome seems to be the main mechanism, which trig-
gers intracellular hyphal formation. This modulation of pha-
gosomal pH requires Stp2p [59], a regulator of amino acid
transport, and members of the ATO gene family for trans-
port of ammonia into the phagosome, which in turn causes
neutralization of the phagosomal pH [60]. Although it has
long been thought that physical piercing of the macrophage
membrane by hyphae is the only cause of macrophage cell
death, two studies have shown that killing by intracellular
C. albicans cells is a two-step mechanism. In fact, C. albicans
triggers pyroptosis, an inflammasome-associated pro-
grammed cell death, before physical forces cause membrane
rupture [61]. The associated interleukin-1β production, how-
ever, seems to be independent of hyphal formation [62]. The
significance of intracellular hyphal formation within macro-
phages was also highlighted by a microevolution
experiment, where the nonfilamentous C. albicans efg1Δ/
cph1Δ mutant was exposed to macrophages for several
months [37]. Intriguingly, a single point mutation within a
gene (SSN3) encoding a component of the Cdk8 module of
the mediator complex, which links transcription factors with
the general transcription machinery (see above), was suffi-
cient to bypass Efg1/Cph1-dependent filamentation.

Finally, as predicted in our previous review, multiple new
compounds have been identified in the last years, some based
on large-scale compound screening [63–65], which inhibit
hyphal formation and, as shown in some studies, the corre-
sponding hyphal-associated properties and virulence. This
included filastatin [66], ascorbic acid [66], mucins [67], gymne-
mic acids [68], and quinacrine [69] to name only a few. Of
note, even known antifungals seem to have specific effects on
the different morphological forms of C. albicans, and one azole
was shown to force the fungus into the yeast growth mode,
potentially due to reduced ergosterol content of the cell
membrane [70]. In agreement with that information, one
study identified ergosterol synthesis as a critical aspect in a
large-scale functional screening to identify regulators of mor-
phogenesis [7].
In summary, hyphal formation and maintenance remain an
area of intensive research with exciting discoveries to be made
that are both relevant for our understanding of fungal biology
and with a great potential to lead to novel adjunctive therapies.
Funding
The authors were supported by the Deutsche Forschungsgemeinschaft
(TR/CRC FungiNet to IDJ, and BH; SPP1580 DFG 528/16 and DFG 528/17 to
BH; and DFG JA 1960/1-1 to IDJ), the Infect ERA-NET Program
(FunComPath; BMBF031L0001A) to BH; the Integrated Research and
Treatment Center for Sepsis Control and Care (CSCC) to IDJ and BH; the
Jena School for Microbial Communication (JSMC), and the International
Leibniz Research School (ILRS) to BH and IJ.
Declaration of interest
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
ORCID
Bernhard Hube http://orcid.org/0000-0002-6028-0425
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