Environment  Health  Techniques

440 Thanwa Wongsuk et al.

Review
Fungal quorum sensing molecules: Role in fungal
morphogenesis and pathogenicity

Thanwa Wongsuk1,3, Potjaman Pumeesat2,3 and Natthanej Luplertlop3,4

1
Department of Clinical Pathology, Faculty of Medicine, Vajira Hospital, Navamindradhiraj University, Bangkok,
Thailand
2
Department of Medical Technology, Faculty of Science and Technology, Bansomdejchaopraya Rajabhat
University, Bangkok, Thailand
3
Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok,
Thailand
4
Center for Emerging and Neglected Infectious Diseases, Mahidol University, Salaya Campus, Nakorn
Pathom, Thailand

When microorganisms live together in high numbers, they need to communicate with each
other. To achieve cellcell communication, microorganisms secrete molecules called quorum-
sensing molecules (QSMs) that control their biological activities and behaviors. Fungi secrete
QSMs such as farnesol, tyrosol, phenylethanol, and tryptophol. The role of QSMs in fungi has
been widely studied in both yeasts and lamentous fungi, for example in Candida albicans,
C. dubliniensis, Aspergillus niger, A. nidulans, and Fusarium graminearum. QSMs impact fungal
morphogenesis (yeast-to-hypha formation) and also play a role in the germination of
macroconidia. QSMs cause fungal cells to initiate programmed cell death, or apoptosis, and
play a role in fungal pathogenicity. Several types of QSMs are produced during stages of biolm
development to control cell population or morphology in biolm communities. This review
article emphasizes the role of fungal QSMs, especially in fungal morphogenesis, biolm
formation, and pathogenicity. Information about QSMs may lead to improved measures for
controlling fungal infection.

Keywords: Quorum-sensing molecules / Morphogenesis / Biofilm

Received: December 16, 2015; accepted: February 19, 2016

DOI 10.1002/jobm.201500759

Introduction Farnesol was the rst QSM isolated from a eukaryotic

Quorum sensing is the ability of microorganisms to
communicate and coordinate their behavior via the
secretion of signaling molecules that accumulate during
their growth in a population dependent manner [1]. Cells
respond to quorum-sensing molecules (QSMs), and when
they reach a critical threshold a regulatory response
occurs that results in the coordinated expression or
repression of quorum-dependent target genes [2]. Quo-
rum sensing has been studied for a long time in the
context of aquatic bioluminescence of Vibrio scheri, and
it has subsequently been observed to regulate many
biological activities in a range of bacterial species [2, 3].
Correspondence: Asst. Prof. Natthanej Luplertlop, Department of
Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol
University, Bangkok 10400, Thailand
E-mail: natthanej.lup@mahidol.ac.th
microorganism, Candida albicans. This was followed by
the later identication of the QSMs tyrosol, phenyl-
ethanol, and tryptophol [2, 4, 5]. QSMs play a role in
morphogenesis, biolm development, limitation of cell
population, and control of nutrient competition, and are
important for the infectious process, especially for the
dissemination and establishment of colonies at distal
locations [69]. Additionally, QSMs have been shown to
induce fungal apoptosis and to modulate host immune
cells. Apoptosis can be induced in several farnesol-
treated fungi, and is characterized by features such as
chromatin condensation, DNA fragmentation, and
changes in ultrastructure, leading to much interest in
the eld about the apoptotic pathways employed by
farnesol-treated fungi [1014]. Furthermore, farnesol
has been shown to affect the differentiation and
cytokine secretion of some immune cells [1518].

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 Quorum sensing in fungi 441

Interestingly, the combination of some QSMs, such as
farnesol and tyrosol, with antifungal drugs, has shown
an impressive increase in efcacy, measured by a
reduction in the mean inhibitory concentration (MIC)
of the tested antifungal drugs [1922].
This review focuses especially on the role of QSMs in
fungal morphogenesis, biolm development, and the
contribution to infection. Understanding the association
between QSMs and fungal pathogenesis could be useful
for controlling fungal infection. A conceptual view of the
interactive relationship between QSMs and fungal cells is
shown in Fig. 1.
Quorum sensing in fungal morphogenesis
An effect of inoculum size on morphogenesis has been
observed for several dimorphic fungi [7]. Budding yeast
cells were formed at cell densities 106 cells/ml and
mycelia were produced at densities <106 cells/ml.
This phenomenon is controlled by QSMs [2, 23]. Farnesol,
the rst QSM identied in a eukaryotic microorganism,
was discovered in C. albicans [8]. Farnesol inhibits yeast-
to-hypha switching but it cannot block the elongation
of preexisting hyphae [7]. However, Lindsay et al. [8]
showed that farnesol could promote the hypha-to-
yeast transition as well. Moreover, pseudohyphae
and hyphae development were inhibited by farnesol in
C. dublinensis [9]. Kebaara et al. [4] showed that Tup1, a
transcriptional repressor of hypha-specic genes, was
increased both at the TUP1 mRNA and protein levels
after treatment of C. albicans cells with farnesol. Hyphal
growth is regulated through several signaling pathways,
in particular the cAMP pathway [2427]. Farnesol
blocked hyphal formation by inhibiting the cAMP
signaling pathway through inhibition of the activity of
Candida adenylyl cyclase, Cyr1p [28]. Additionally,
Sato et al. [29] observed that the mitogen-activated
protein (MAP) kinase cascade was inhibited in farnesol-
treated C. albicans cells. Moreover, C. albicans ATCC 10231
released farnesoic acid into the culture medium, which
also inhibited lamentous growth [30]. Farnesol also
had an effect on the conidiation, germination, and
hyphal morphology of several fungi [31, 32]. In Aspergillus
niger, high concentrations of farnesol inhibited con-
idiation and reduced intracellular cAMP levels, but did
not inhibit aerial hyphae production [31]. In addition,
the development and germination of macroconidia of

Figure 1. A conceptual view of the interactive relationship between QSMs and fungal cells. When QSMs are produced from fungal cells
(including exogenous QSMs) and reach a critical threshold, a regulatory response occurs, resulting in the coordinate expression or repression
of quorum-dependent target genes. QSMs affect morphogenesis and biolm development, regulate defense against fungal invasion during
infection, induce apoptosis, and act as antifungal agents on fungal cells.

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442 Thanwa Wongsuk et al.
Fusarium graminearum, a plant fungal pathogen, were
impaired by farnesol treatment [12]. The amount of
ergosterol decreased in farnesol-treated cells and af-
fected the integrity of the fungal plasma membrane in
Coccidioides posadasii [33]. Moreover, Derengowski
et al. [34] showed that the fungicidal properties of
farnesol were associated with the degradation of
cytoplasmic organelles but not cell walls or plasma
membrane. Farnesol also affects C. albicans metabolic
pathways, including several pathways associated with
morphogenesis and pathways associated with other
functions [35].
Tyrosol is another quorum-sensing molecule secreted
by C. albicans, and is continuously released into the
culture medium during growth, playing a role in the
promotion of germ tube formation [5]. Additionally,
several alcohols have been found in planktonic cells and
biolm supernatants from C. albicans and C. dubliniensis.
These include isoamyl alcohol, 2-phenylethanol,
1-dodecanol, E-nerolidol, and E,E-farnesol, which are
species, culture mode and growth time specic, and
play a role in morphogenesis [36]. Additionally, the
production of autosignaling alcohols, tryptophol, and
phenylethylalcohol, which promote pseudohyphal
growth in Saccharomyces cerevisiae, was regulated by
nitrogen availability and cell density and could not
stimulate lamentation in C. albicans; this indicates that
these signals are species-specic [37]. Moreover, several
alcohols were able to inhibit yeast-to-hypha switching
of C. albicans in a concentration-dependent manner [38].
Phenylethanol and tyrosol were also detected in
Debaryomyces hansenii depending on the cell density
and environmental conditions [39].
Effect of quorum sensing in fungal biolm
development
Biolms are well-structured microbial communities
attaching to biotic or abiotic surfaces surrounded by
extracellular polymeric substance (EPS) [40, 41]. Several
fungi have been reported to form biolms, especially
on medical devices. This leads to an increase in infection
and mortality because biolms are more resistant
than planktonic cells to many antifungal drugs [42].
Fungal biolm formation has been widely studied in
C. albicans [41, 4347]. During biolm development of
C. albicans, yeast cells play a role in the initial attachment
to the surface; this is followed by formation of
laments, and nally a mature biolm forms, compris-
ing yeast, true hyphae, pseudohyphae, and EPS [4547].
This implies that morphology plays a role in
biolm development. QSMs also control the formation
of C. albicans biolms. Farnesol inhibited biolm
2016 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim
development concomitant with a decrease in HWP1
(encoding hypha-specic wall protein) expression,
reecting the morphological characteristics of the
cells [48]. Moreover, supernatant recovered from bio-
lms can inhibit hyphal formation of C. albicans
planktonic cells, which demonstrate the presence of
autoregulatory molecules produced by biolms [48].
Under anaerobic conditions, farnesol is not pro-
duced [29], but other alcohol-based autoregulating
substances produced in these conditions can promote
the dissemination of yeast cells from the biolm,
thereby inhibiting biolm development [38]. The attach-
ment of fungal cells on surfaces is the rst step of biolm
development and QSMs play an important role in
this. Phenylethanol and tyrosol increased the ability of
D. hansenii to attach to polystyrene while tryptophol and
farnesol reduced this ability and also inuenced the
sliding motility of this organism [39], demonstrating the
inuence these molecules have on biolm formation.
QSMs regulate defense against fungal invasion
during infection
QSMs play a role in the defense against fungal invasion.
QSMs can induce oxidative stress in macrophages.
Effector activity of macrophages against C. albicans was
reduced in farnesol-treated murine macrophages and
farnesol also induced cell death and apoptosis via
intracellular reactive oxygen species (ROS) produc-
tion [15]. Joo et al. mentioned that apoptosis in lung
carcinoma cells was induced by farnesol in cooperation
with endoplasmic reticulum (ER) stress [49]. They also
reported that farnesol induced inammatory genes
through the stimulation of the NF-kB pathway, including
MEK1/2-ERK1/2-MSK1-dependent phosphorylation of
p65/RelA(Ser276) [50, 51]. In in vitro studies, farnesol
is able to protect C. albicans from ROS [52]. Deveau
et al. proposed that farnesol increased ROS resistance in
C. albicans through suppression of the Ras1-cAMP path-
way [51, 53]. Other QSMs have also been shown to have an
effect on immune cells: tyrosol altered neutrophilic
killing by inhibiting the respiratory burst [54]. Thus,
these experiments support the suggestion that QSMs play
an important role in virulence in fungal infection.
Ghosh et al. explained that wild-type C. albicans can
escape from macrophages within 6 h via stimulation of
arginine biosynthesis, which induces yeast-to-hypha
formation [16]. They also evaluated cytokine production
in the murine RAW264.7 macrophage cell line and
showed that the expression of IL-6 was decreased in
farnesol-treated cells [17]. Therefore, farnesol plays a key
role as a virulence factor of fungal infection. Moreover,
in a mouse model of Candida infection, farnesol also
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 Quorum sensing in fungi 443

Table 1. Role of QSMs on yeasts.

Organism QSMs Role of QSMs on yeast cells References

C. albicans Farnesol - Inhibited hyphal development [7, 23]
- Played role in morphogenesis [36]
- Inhibited biofilm formation [48]
- Induced apoptosis [13]
- Antifungal activity [67]
- Modulated drug extrusion [62]
Tyrosol - Promoted germ tube formation [5]
- Stimulated hypha production during the early stages [3]
of biofilm development
- Antifungal activity [19]
Isoamyl alcohol - Played role in morphogenesis [36]
2-Phenyl ethanol
1-Dodecanol
E-nerolidol
C. dubliniensis Farnesol - Inhibited hyphal development [9]
- Played role in morphogenesis [36]
- Inhibited biofilm formation [57]
- Antifungal activity [57]
Isoamyl alcohol - Played role in morphogenesis [36]
2-Phenyl ethanol
1-Dodecanol
E-nerolidol
C. tropicalis Farnesol - Antifungal activity [20]
Tyrosol - Antifungal activity [19]
C. krusei Tyrosol - Antifungal activity [19]
S. cerevisiae Tryptophol - Promoted pseudohyphal growth [37]
Phenyl ethanol
D. hanseii Farnesol - Played role in adhesion and sliding motility [39]
Tyrosol
Tryptophol
Phenyl ethanol

inhibited IFN-g and IL-12 (Th1 cytokines), which are
produced by macrophages to promote systemic candidi-
asis immunity [18]. Navarathna et al. found that
pathogenicity of systemic candidiasis was reduced when
endogenous farnesol was reduced. This was due to the
deciency of a phosphatase-encoding gene, which
prevented the conversion of farnesyl pyrophosphate to
farnesol [55]. Additionally, Leonhardt et al. addressed
another characteristic of farnesol in C. albicans virulence.
Farnesol activated innate immune cells, including
neutrophils and monocytes, leading to enhanced in-
ammation, but inhibited the differentiation of mono-
cytes into immature dendritic cells [56].
Farnesol induces apoptosis in yeasts and lamentous
fungi
In addition to its effects on immune cells, exogenous
farnesol has been shown to block the yeast-to-hypha
transition and biolm development at the premature
stages in a concentration-dependent manner (high
concentrations) [48, 57, 58]. Jabra-Rizk et al. showed
that high concentrations of farnesol also induce cell
death in C. albicans [57]. As a result, farnesol was able to
induce apoptosis in several fungi. In C. albicans, Shirtliff
et al. used a proteomic approach coupled with detection
of apoptosis markers on farnesol-treated cells. They
found that apoptosis was induced via caspase stimula-
tion [13]. Additionally, L
eger et al. investigated the role of
the metacaspase Mca1p in the mechanism of farnesol-
induced apoptosis. Mca1p was involved in the apoptosis
pathways of both mca1 disruption and farnesol-treated
cells [14]. Furthermore, farnesol may interact at another
point in the programmed cell death pathway by altering
the levels of intracellular glutathione S-conjugate (F-GS)
combined with transporter protein (Cdr1-p). This results
in the decrease of intracellular reduced glutathione
(GSH), leading to the activation of apoptosis pathways
and fungal cell death [59].
A number of studies have investigated the mechanisms
of farnesol treatment of other lamentous fungi. Similar to
in C. albicans, farnesol induced apoptosis in A. nidulans [10],
A. avus [11], P. expansum [32], F. graminerum [12], Scedosporium
boydii (unpublished TW, PP, NL), and Lomentospora prolicans
(unpublished TW, PP, NL). In A. nidulans, Semighini et al.

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444 Thanwa Wongsuk et al.

Table 2. Role of QSMs on molds and dimorphic fungi.

Organism QSMs Role of QSMs on molds and dimorphic fungi References

A. nidulans Farnesol - Induced apoptosis [10, 60, 61, 68]
- Oxidative and heat stress resistance [69]
A. niger Farnesol - Inhibited conidiation [31]
- Reduced intracellular cAMP levels
A. fumigatus Farnesol - Altered growth phenotype [70]
- Perturbed cell wall
A. flavus Farnesol - Induced apoptosis [11]
C. posadasii Farnesol - Antifungal activity [33]
- Decreased the amount of ergosterol
- Affected the integrity of plasma membrane
F. graminearum Farnesol - Induced apoptosis [12]
- Inhibited germination of macroconidia
- Decreased viability
H. capsulatum Farnesol - Inhibited biofilm formation [66]
- Antifungal activity
P. brasiliensis Farnesol - Inhibited growth [34]
- Delayed the dimorphic transition
- Antifungal activity
P. expansum Farnesol - Induced apoptosis [32]
- Inhibited growth
P. destructans Farnesol - Inhibited growth [71]
S. boydii Farnesol - Induced apoptosis Our study
- Inhibited growth
L. prolificans Farnesol - Induced apoptosis Our study
- Inhibited growth

demonstrated that apoptosis was activated through ROS
and the FadA heterotrimeric G protein complex [10].
Apoptosis-Inducing Factor (AIF)-like mitochondrial oxido-
reductase and NADH-ubiquinone oxidoreductases (NdeA-B
and NdiA) have both been implicated in compensatory
pathways of farnesol-induced ROS and apoptosis [60, 61].
Furthermore, Wang et al. detected apoptosis markers
(nuclear condensation, phosphatidylserine, externaliza-
tion, DNA fragmentation, ROS, metacaspase activation,
and cellular ultrastructure changes) in A. avus treated with
farnesol [11]. There is only one study in a fungal plant
pathogen, F. graminerum, where farnesol also stimulated
apoptosis [12]. In our study (data not shown, submitted), we
found that farnesol-treated cells of S. boydii and L. prolicans
led to the condensation of chromatin and orange staining of
cells by ethidium bromide/acridine orange, which indicated
apoptosis. Thus, farnesol may activate the apoptosis
pathway in both S. boydii and L. prolicans; however, more
work needs to be done to determine the precise mechanism
by which this is achieved.
QSMs as antifungal agents
QSMs have been investigated as antifungal agents. Shama
et al. showed that farnesol could modulate drug extrusion,
mediated by ABC transporters such as CaCdr1p
and CaMdr1p, without affecting the major facilitator
superfamily (MFS) transporters such as CaMdr1p. This
synergistic effect was also observed with farnesol and
antifungal drugs (azoles and polyenes) in C. albicans [62].
Therefore, a nontoxic concentration of farnesol may be
used as an alternative anti-C. albicans. As in Candida species,
when farnesol was combined with antifungal agents, the
MIC was decreased compared with antifungal agents
alone [20]. A number of studies have demonstrated the
requirement for a high MIC for treatment of C. albicans
biolms (reviewed in Taff et al. [63] and Chandra et al. [64]).
Katragkou et al. showed a synergistic effect of farnesol
combined with a number of antifungal agents (ucona-
zole, amphotericin B, and micafungin) against C. albicans
biolms [21]. Sterol biosynthesis mechanisms may be
involved in reducing uconazole resistance in farnesol-
treated C. albicans biolms by repressing the ERG11, ERG25,
ERG6, ERG3, and ERG1 genes regulating ergosterol
biosynthesis [65]. Similar to farnesol, tyrosol was investi-
gated in combination with antifungal agents and showed a
synergistic effect when combined with amphotericin B
(90% reduction in C. krusei biolm and C. tropicalis biolm
when 80 mM tyrosol was coupled with 4 mg/L amphoteri-
cin B) [22]. Cordeiro et al. reported that exogenous tyrosol
alone or combined with amphotericin B inhibited
planktonic cells and Candida biolm growth. Interest-
ingly, mature biolms were also inhibited by tyrosol
alone or combined with amphotericin B, but tyrosol
combined with azoles increased the biolm activity in a

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dose-dependent manner [19]. In dimorphic fungi, Der-
engowski et al. showed the in vitro activity of
farnesol against P. brasiliensis (an average MIC around
25 mM and minimal lethal concentration around
30 mM) [34]. The combination of farnesol with antifungal
drugs showed synergistic effects (fractional inhibitory
concentration index [FICI] 0.5) in C. posadasii [33] and
H. capsulatum [66].
Conclusions
In fungi, QSMs are key molecules in cell-to-cell signaling,
function and communication. In recent years, there has
been much interest in the basic characterization of
QSMs in fungi, especially in C. albicans and Aspergillus
spp. QSMs are small molecules that are released from
cells, act as autoinducers and regulate the community,
dependent on the concentration of the cell popula-
tion [72]. Here, we have provided an overview of the
mechanisms of fungal quorum sensing and its associated
functions (fungal morphogenesis, fungal biolm devel-
opment, and fungal pathogenicity). Ultimately, better
understanding of the role of quorum sensing in
fungi will help us to understand the mechanisms or
pathways that are important in human fungal infection.
Moreover, this knowledge may result in the development
of alternative treatments to protect against invasive
mycoses. Tables 1 and Table 2 show the major roles of
QSMs on yeasts, molds, and dimorphic fungal cells.
Acknowledgments
This review article is supported by the Ofce of the
Higher Education Commission and Mahidol University
under the National Research Universities Initiative,
Trop. Med. Grants 2013 and 2014, Faculty of Tropical
Medicine, Mahidol University.
Conict of interest
The authors report no conicts of interest.
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