Curr Genet
DOI 10.1007/s00294-017-0683-x
REVIEW
Quorum sensing by farnesol revisited
Melanie Polke1 · Ilse D. Jacobsen1,2,3 
Received: 26 January 2017 / Revised: 1 February 2017 / Accepted: 7 February 2017
© Springer-Verlag Berlin Heidelberg 2017
Abstract  Quorum sensing, a form of molecular com-
munication in microbial communities, is relatively well
studied in bacterial species, but poorly understood in
fungi. Farnesol, a quorum sensing molecule secreted by
the opportunistic human pathogenic fungus Candida albi-
cans, was the first quorum sensing molecule described in
a eukaryotic organism. However, despite considerable
research efforts and advances in recent years, the mecha-
nisms behind its action remain largely elusive. Only
recently, we showed that deletion of the C. albicans gene
EED1 (eed1Δ), which is essential for hyphal maintenance,
resulted in both increased farnesol production and hyper-
sensitivity to farnesol, providing a link between farnesol
signaling and elongated hyphal growth. This finding raised
several questions concerning farnesol signaling. In this
short review we use the unique phenotype of the eed1Δ
mutant to summarize current hypotheses and to speculate
on possible mechanisms of quorum sensing in C. albicans
and its implication in fungus–host interaction, by drawing
comparisons to comparatively well-studied quorum sensing
systems in bacteria.
Communicated by M. Kupiec.
* Ilse D. Jacobsen
ilse.jacobsen@leibniz‑hki.de
1
Research Group Microbial Immunology, Leibniz Institute
for Natural Product Research and Infection Biology, Hans
Knoell Institute (HKI), Beutenbergstrasse 11a, 07745 Jena,
Germany
2
Friedrich Schiller University, Jena, Germany
3 true hyphae is considered one of the major virulence traits of
Integrated Research and Treatment Center, Center for Sepsis
Control and Care (CSCC), University Hospital, Jena,
Germany
Keywords  Quorum sensing · Candida albicans ·
Farnesol · EED1 · Bacteria
Introduction
Most microorganisms live in complex environments that
they share with numerous other microbial, protozoan and
multicellular organisms. In order to survive, they have to
sense not only their environment, but also organize behavior
on a population basis. This is commonly mediated by small
secreted molecules that accumulate depending on cell den-
sity, and upon reaching a threshold, influence cell behavior,
a mechanism termed quorum sensing (QS). Since the discov-
ery of QS in Vibrio fischeri in 1970 (Nealson et al. 1970), QS
systems were identified in a large number of bacterial species
(Kimura 2014), including a wide range of human pathogens
where they regulate important virulence traits reviewed in
Williams et  al. (2000), Miller and Bassler (2001), Bassler
(2002), Antunes et al. (2010), Rutherford and Bassler (2012),
Castillo-Juarez et  al. (2015), and Yang and Lan (2016). QS
has long been suspected to also occur in fungi (Yen and How-
ard 1970; Hazen and Cutler 1979), and the first quorum sens-
ing molecule (QSM) identified in a eukaryotic organism was
farnesol in the polymorphic yeast Candida albicans (Hornby
et al. 2001). C. albicans is an opportunistic human pathogen
that occurs as a commensal on the mucosal surfaces in the
majority of the healthy human population (Odds 1987; Kim
and Sudbery 2011). Importantly, C. albicans is a pleomor-
phic fungus that can grow as budding yeast and also form
filaments under a wide variety of conditions (Biswas et  al.
2007; Sudbery 2011; Du and Huang 2016). The formation of
C. albicans (Kumamoto and Vinces 2005) and this is affected
by farnesol: farnesol inhibits the yeast-to-hypha transition
13
Vol.:(0123456789)

(Hornby et  al. 2001) and promotes reverse morphogenesis,
the production of budding yeast from hyphae (Zhang et  al.
2011; Lindsay et  al. 2012; Polke et  al. 2016). Because of
this, and since farnesol also acts synergistically with antifun-
gal therapy (Yu et al. 2012; Cordeiro et al. 2013; Katragkou
et  al. 2015), it has been proposed as adjunctive therapeutic
agent (Hornby et al. 2001). However, farnesol also affects the
mammalian host and actually promotes pathogenesis (Navar-
athna et al. 2007a, b), possibly due to its detrimental effects
on immune cells (Navarathna et al. 2007b; Abe et al. 2009;
Ghosh et al. 2010; Leonhardt et al. 2015). In addition to inter-
action with its host, as a commensal C. albicans has to com-
pete and interact with other fungi and a plethora of bacterial
species that inhabit the same host niches. QSMs are major
chemical mediators of communication between microbes in
this complex environment. Farnesol produced by C. albicans
has profound inhibitory effects on various fungi and bacteria
(recently reviewed in Langford et  al. (2009), Shirtliff et  al.
(2009b), Dixon and Hall (2015), and Allison et  al. (2016)).
In turn, bacterial QSMs such as N-acyl homoserine lactones
(AHL), certain cis-unsaturated fatty acids termed diffus-
ible signal factors (Ryan and Dow 2011), and autoinducer-2
(cyclic oligopeptides, Sun et  al. 2004) from bacteria act on
C. albicans (recently reviewed in Dixon and Hall (2015) and
Allison et al. (2016)). However, the mechanisms underlying
these interactions and the complexity of the communication
are only incompletely understood. Furthermore, the molecu-
lar basis of farnesol signaling in C. albicans populations
remains, despite intensive research in recent years, largely
elusive.
We recently discovered that deletion of C. albicans
EED1, which is essential for hyphal maintenance (Zakikh-
any et al. 2007; Martin et al. 2011), results in both farnesol
hypersensitivity and enhanced farnesol production (Polke
et al. 2016). Thus, we described the first C. albicans strain
hypersensitive to the QSM, and provided another link of
farnesol signaling and hyphal maintenance regulation.
While many questions about the eed1Δ phenotype remain,
the mutant may be an attractive tool for future farnesol
research, as pointed out in detail by Nickerson and Atkin
(2016). In this short review, we focus on the eed1Δ phe-
notype to speculate on some open questions regarding
farnesol signaling in C. albicans by drawing comparisons
to the comparably well-studied mechanisms in bacterial
communication.
Farnesol: the open questions on fungal quorum
sensing and lessons from bacteria
In bacteria, QS systems often include multiple intersect-
ing signaling pathways, which may act in parallel or in a
hierarchical manner (Lee and Zhang 2015; Hawver et  al.
13
Curr Genet
2016). However, the basic principle of bacterial QS sys-
tems appears to be conserved: they consist of an enzyme
which catalyzes production of the active QSM, and a recep-
tor for the QSM, which directly or indirectly reprograms
the cellular gene expression resulting in a cellular response.
Much less is known about farnesol signaling in C. albicans:
farnesol is produced as a byproduct of the ergosterol syn-
thesis in C. albicans (Hornby et  al. 2003), however, the
exact mechanism of farnesol production from its precursor
farnesol pyrophosphate remains poorly understood. While
the pyrophosphatase Dpp3 has been implicated in mediat-
ing farnesol production (Navarathna et  al. 2007a; Zhang
et  al. 2011; Chang et  al. 2012), farnesol levels were not
decreased by deletion of DPP3 in a C. albicans SC5314
wild type background (Polke et al. 2016), implicating that
further pyrophosphatases are involved (Nickerson and
Atkin 2016; Polke et al. 2016). DPP2 and DPP1 have been
suggested as candidates (Navarathna et al. 2007a; Ganguly
et al. 2011; Polke et al. 2016); however, experimental proof
linking these genes encoding for phosphatases to farnesol
production is lacking.
Most QSMs freely diffuse over the bacterial membrane;
however, active transport is necessary for AI-2, short oli-
gopeptide QSMs secreted by Gram-positive bacteria (Jime-
nez and Federle 2014; Monnet et  al. 2014). It has also
been described for other bacterial QSM, e.g. the Pseu-
domonas aeruginosa QSM 3-oxo-C12-homoserine lactone
(3OC12HSL) (Pearson et  al. 1999), which is structurally
related to farnesol. While it remains unknown if such a
transport mechanism exists for farnesol in C. albicans, the
increased secretion of the QSM in a C. albicans eed1Δ
mutant could be explained by the existence and heightened
activity of an active farnesol transport system (Nickerson
and Atkin 2016). Extracellular farnesol levels in C. albi-
cans can exceed the intracellular concentrations (Navar-
athna et al. 2005; Polke et al. 2016), suggesting the exist-
ence of active farnesol exporters, as freely diffusible QSMs
accumulate both intracellularly and in the extracellular
space (Bassler 2002). An active export may also explain
why the farnesol tolerance of C. albicans is energy depend-
ent (Langford et al. 2010), as decreased export may result
in a rapid intracellular accumulation of the QSM which
could promote cell death induction due to disturbance of
intracellular processes (Machida and Tanaka 1999; Shirtliff
et  al. 2009a; Dichtl et  al. 2010; Zhu et  al. 2011; Leger
et al. 2015). Furthermore, increased farnesol export would
change the equilibrium between intra- and extracellular
farnesol, and thereby stimulate increased farnesol produc-
tion (Navarathna et al. 2005; Langford et al. 2009; Nicker-
son and Atkin 2016).
Increased farnesol secretion in eed1Δ does, however,
not explain the heightened sensitivity of the C. albi-
cans eed1Δ mutant to farnesol. It appears possible that
Curr Genet
the hypersensitivity to the QSM, which has not yet been
described for any other C. albicans mutant, is a result of
a decreased farnesol threshold, for example by increased
expression of a farnesol receptor, as discussed by Nicker-
son and Atkins (2016). In bacteria both, intracellular and
surface localized receptors for QSMs have been described
(Cao and Meighen 1989; Bassler et  al. 1993; Lina et  al.
1998; Swem et  al. 2008; LaSarre and Federle 2013;
Hawver et  al. 2016), but a farnesol receptor in C. albi-
cans has not yet been identified. However, farnesol exerts
multiple effects in C. albicans, as it targets several factors
involved in the regulation of morphogenesis, such as the
adenylyl cyclase Cyr1 (Davis-Hanna et al. 2008; Hall et al.
2011), and the small GTPase Ras1 (Piispanen et al. 2013).
Further regulators involved in farnesol signaling are NRG1,
TUP1, CHK1 and CZF1, deletion of which reduces or
abolishes the effects of farnesol on filamentation (Kruppa
et al. 2004; Kebaara et al. 2008; Langford et al. 2013), as
well as Efg1, Cek1 and Hog1 (Roman et al. 2009; Deveau
et  al. 2010; Langford et  al. 2013). Farnesol may direct its
multiple effects by binding to several targets, or via a com-
mon receptor which regulates different downstream targets.
The observed eed1Δ phenotype could be explained if Eed1
would negatively control the activity and/or stability of
such a sensor. Interestingly, the bacterial LuxR-type recep-
tor protein, a component of the LuxI-LuxR-type QS sys-
tem present in many Gram-negative bacteria (Fuqua et al.
1994), has been shown to be regulated by binding of the
QSM AHL itself: in the absence of its ligand only a small
percentage of LuxR receptors is stable, while the majority
of the receptor molecules are rapidly degraded (Sappington
et al. 2011; Hawver et al. 2016). In the presence of sufficient
AHL levels, its binding to LuxR stabilizes the complex and
structural rearrangements subsequently allow DNA bind-
ing and induction of QS-mediated functions (Hawver et al.
2016). In contrast, in the Bacillus subtilis Rap-Phr sys-
tem the QS receptor Rap becomes inactivated by binding
of the QSM (Pollak et  al. 2015). Thus, it is intriguing to
speculate that if a specific farnesol receptor exists, it may
be partially stable without ligand binding, but prone to deg-
radation when farnesol is not present in appropriate con-
centrations. Eed1 could be directly or indirectly involved in
directing this receptor for degradation, so that the receptor
would be stabilized in an eed1Δ mutant, and consequently
lower levels of farnesol may elicit a great response within
the cell in a more rapid fashion. In bacterial QS systems
it is furthermore common that QSM signaling also acti-
vates the genes encoding the enzymes necessary for QSM
production (Rutherford and Bassler 2012; Castillo-Juarez
et al. 2015). While this has not been described for farnesol
signaling (Cao et  al. 2005; Enjalbert and Whiteway
2005; Cho et  al. 2007), a positive feedback-loop between
farnesol signaling and production would explain both, the
farnesol hypersensitivity and increased farnesol produc-
tion by eed1Δ (Polke et al. 2016). The hypothesis of a spe-
cific farnesol receptor protein is furthermore supported by
the observation that eed1Δ is hypersensitive exclusively
to farnesol, but not 3OC12HSL: while the action of both
molecules seems to be quite similar, as farnesol affects
virulence factor production in P. aeruginosa (Cugini et al.
2007, 2010; McAlester et al. 2008), and both molecules are
able to inhibit morphogenesis in C. albicans (Hogan et al.
2004; Hall et al. 2011), the finding that eed1Δ is hypersen-
sitive only to farnesol suggests that despite similar modes
of action, farnesol and 3OC12HSL may be differentially
transported and/or sensed in C. albicans.
Assuming that the filament inhibitory action of farnesol
is mediated via a specific sensor/receptor, while cell death
is likely induced by rather unspecific farnesol effects (e.g.
membrane disturbances, glutathione extrusion, etc. Bring-
mann et al. 2000; Scheper et al. 2008; Zhu et al. 2011), the
increased expression of a farnesol receptor in eed1Δ would
also explain, why the mutant is solely sensitive to the fila-
ment inhibitory action, but not to cell death induction by
farnesol (Polke et al. 2016). Indeed it has been speculated
that the various effects of farnesol require different molecu-
lar mechanisms (Nickerson et al. 2006).
The role of quorum sensing during host–fungal
interactions
It has been suggested that quorum sensing in bacterial pop-
ulations assures a delay in virulence factor expression until
a certain population density is reached. This maximizes the
probability to establish a successful infection. Assuming
that this is the purpose of QS in C. albicans, why would
the fungus downregulate hypha-formation, one of its most
important virulence traits (Kumamoto and Vinces 2005), at
high cell densities? Is this simply a protective mechanism
to reduce energy expenditure at high cell densities when
nutrients become limited? This is a plausible explanation
in complex communities such as biofilms, where nutrients
likely get limited once the population reaches a certain
size (Ramage et  al. 2002). It is tempting to speculate that
C. albicans may exploit the regulation of genes which have
been implicated in regulating filamentation and the sensi-
tivity to farnesol, e.g. CZF1, NRG1 and EED1 (Kebaara
et  al. 2008; Langford et  al. 2013; Polke et  al. 2016), as a
self-regulatory mechanism to induce yeast budding from
filaments in mature biofilms to induce dispersal and seed-
ing of new niches. Based on the eed1Δ mutant pheno-
type, down-regulation of EED1 could facilitate enhanced
dispersal by increasing farnesol production and enhanc-
ing farnesol sensitivity, thereby promoting the transi-
tion to yeast growth. Comparable mechanisms have been
13

described for bacterial pathogens: biofilm development of
Staphylococcus aureus is inhibited by the bacterial agr QS
system. Therewith the QS system promotes both, virulence
factor expression and dispersal of cells from the biofilm
at high cell densities by decreasing surface proteins and
adhesins (Vuong et  al. 2000; Yarwood et  al. 2004; Boles
and Horswill 2008). It would not be surprising, if fungi
would have developed comparable systems to control their
dispersion and dissemination.
On the other hand, hyphal growth may not be abso-
lutely required for C. albicans under the conditions when
a high cell density is reached, and/or the secretion of the
immunomodulatory farnesol may itself promote virulence
(Navarathna et al. 2007b; Abe et al. 2009; Leonhardt et al.
2015). Furthermore, C. albicans co-colonizes and infects
host niches, which are occupied by a wide range of other
microbes. As described above, farnesol has strong antifun-
gal and antibacterial activities against a range of different
organisms (Machida and Tanaka 1999; Jabra-Rizk et  al.
2006; Langford et  al. 2009; Albuquerque and Casadevall
2012), and, likewise, bacteria can inhibit C. albicans fila-
mentation or induce cell death by producing small sign-
aling molecules or toxins (Morales et  al. 2010, 2013). In
many of the bacteria–Candida interactions studied, hyphae
are specifically prone to bacterial attack (Hogan and Kolter
2002; Brand et al. 2008; Mear et al. 2013). Self-regulation
of hypha-formation at high densities may therefore be a
protective mechanism exploited by C. albicans to cope
with bacterial competitors, but also the host immune sys-
tem as yeast are generally better tolerated than hyphae
(White et  al. 2007; Moyes et  al. 2010; Pierce and Kuma-
moto 2012).
An important point when discussing putative roles of
farnesol in the host is farnesol production by C. albicans
in  vivo: while bacterial QSMs have been readily detected
in patient samples (Geisenberger et  al. 2000; Singh et  al.
2000; Favre-Bonte et  al. 2002), it remains unknown, if
and to what amount farnesol is produced by C. albicans in
the host. The quantification of farnesol production by C.
albicans in  vivo is complicated as the molecule is also a
common byproduct in cholesterol and isoprenoid synthesis
in mammalian cells (Parmryd and Dallner 1996; Joo and
Jetten 2010). Previous studies which aimed to analyze the
influence of farnesol production in vivo used farnesol over-
producing C. albicans (Navarathna et al. 2005) or a dpp3Δ
deletion strain (Navarathna et al. 2007a). Farnesol produc-
tion in  vivo was, however, not per se analyzed. Thus it is
possible that farnesol production of C. albicans in the host
differs substantially from that measured during in  vitro
growth. Consequently, it remains unknown if the amounts
of farnesol produced by the fungus in  vivo are sufficient
to block germ tube formation. It is possible that in  vivo
farnesol concentrations never rise high enough, since the
13
Curr Genet
molecule is absorbed by surrounding host membranes,
degraded by host enzymes, or sequestered/inactivated by
other microbes (Hogan 2006; Nickerson et  al. 2012). In
addition QS signaling in vivo will likely not only be shaped
by the fungal QSMs secreted, but also by host molecules,
environmental conditions and the presence or absence of
other bacterial and fungal species, as it was described for
bacterial QS systems (Williams et  al. 2000; Waters and
Bassler 2005; Jensen et  al. 2006; Sarkisova et  al. 2014;
Jung et  al. 2015; Lee and Zhang 2015). For AHL mole-
cules from P. aeruginosa it was shown that while playing
an important role for virulence in in  vitro models, around
50% of clinical isolates from cystic fibrosis patient lungs
were deficient for this QS system (Winstanley and Fother-
gill 2009), implicating that QS systems may play different
roles in distinct in vivo settings. Comparable studies on C.
albicans infections could provide information about the
importance of fungal QS during infection in the host; how-
ever, such studies will not be possible until the mechanisms
underlying fungal QS are better explored and appropriate
tools have been developed.
Conclusion and future perspective
Despite recent insights into farnesol signaling in C. albi-
cans, the basic principles of the molecular interactions
involved and the impact of farnesol on interaction with
the host remain largely in the dark. We know from bac-
teria that QS can be very complex (Lee and Zhang 2015;
Jung et  al. 2016), and that it not just promotes a specific
behavioral adaptation depending on cell density, but also
allows to integrate information about the presence of other
microbes. While QS inhibition methods have been explored
for various pathogenic bacteria (Niu et  al. 2006; Balaban
et al. 2007; Schramm et al. 2008; Sharma and Jangid 2014;
Castillo-Juarez et  al. 2015), the lack of knowledge on the
mechanisms behind fungal QS have hindered comparable
approaches. We first have to understand fungal QS better
before we can rationalize using QSMs or quorum quench-
ing as therapeutic option in fungal infections (Hogan 2006;
Nickerson et al. 2006; Scutera et al. 2014; Sharma and Jan-
gid 2014; Yada et al. 2015).
Acknowledgements  This work was financially supported by the
Studienstiftung des deutschen Volkes e.V. (to MP) and the Deutsche
Forschungsgemeinschaft (DFG JA1960/1-1, to IDJ).
References
Abe S et  al (2009) Suppression of anti-Candida activity of mac-
rophages by a quorum-sensing molecule, farnesol, through
Curr Genet
induction of oxidative stress. Microbiol Immunol 53:323–
330. doi:10.1111/j.1348-0421.2009.00128.x
Albuquerque P, Casadevall A (2012) Quorum sensing in fungi: a
review. Med Mycol 50:337–345. doi:10.3109/13693786.2011
.652201
Allison DL, Willems HM, Jayatilake JA, Bruno VM, Peters BM,
Shirtliff ME (2016) Candida-bacteria interactions: their
impact on human disease Microbiol Spectr. doi:10.1128/
microbiolspec.VMBF-0030-2016
Antunes LC, Ferreira RB, Buckner MM, Finlay BB (2010) Quorum
sensing in bacterial virulence. Microbiology 156:2271–2282.
doi:10.1099/mic.0.038794-0
Balaban N et  al (2007) Treatment of Staphylococcus aureus bio-
film infection by the quorum-sensing inhibitor RIP. Anti-
microb Agents Chemother 51:2226–2229. doi:10.1128/
AAC.01097-06
Bassler BL (2002) Small talk. Cell-to-cell communication in bacteria.
Cell 109:421–424
Bassler BL, Wright M, Showalter RE, Silverman MR (1993) Inter-
cellular signalling in Vibrio harveyi: sequence and function of
genes regulating expression of luminescence. Mol Microbiol
9:773–786
Biswas S, Van Dijck P, Datta A (2007) Environmental sensing and
signal transduction pathways regulating morphopathogenic
determinants of Candida albicans. Microbiol Mol Biol Rev
71:348–376. doi:10.1128/MMBR.00009-06
Boles BR, Horswill AR (2008) Agr-mediated dispersal of Staphylo-
coccus aureus biofilms. PLoS Pathog 4:e1000052. doi:10.1371/
journal.ppat.1000052
Brand A, Barnes JD, Mackenzie KS, Odds FC, Gow NA (2008)
Cell wall glycans and soluble factors determine the interac-
tions between the hyphae of Candida albicans and Pseu-
domonas aeruginosa. FEMS Microbiol Lett 287:48–55.
doi:10.1111/j.1574-6968.2008.01301.x
Bringmann A, Skatchkov SN, Faude F, Enzmann V, Reichenbach A
(2000) Farnesol modulates membrane currents in human reti-
nal glial cells. J Neurosci Res 62:396–402. doi:10.1002/1097-
4547(20001101)62:3<396::AID-JNR10>3.0.CO;2-E
Cao JG, Meighen EA (1989) Purification and structural identification
of an autoinducer for the luminescence system of Vibrio har-
veyi. J Biol Chem 264:21670–21676
Cao YY et  al (2005) cDNA microarray analysis of differential gene
expression in Candida albicans biofilm exposed to farnesol.
Antimicrob Agents Chemother 49:584–589. doi:10.1128/
AAC.49.2.584-589.2005
Castillo-Juarez I et  al (2015) Role of quorum sensing in bacterial
infections. World J Clin Cases 3:575–598
Chang W, Li Y, Zhang L, Cheng A, Lou H (2012) Retigeric acid B
attenuates the virulence of Candida albicans via inhibiting ade-
nylyl cyclase activity targeted by enhanced farnesol production.
PLoS One 7:e41624. doi:10.1371/journal.pone.0041624
Cho T, Aoyama T, Toyoda M, Nakayama H, Chibana H, Kaminishi
H (2007) Transcriptional changes in Candida albicans genes
by both farnesol and high cell density at an early stage of mor-
phogenesis in N-acetyl-D-glucosamine medium Nihon Ishinkin
Gakkai Zasshi 48:159–167
Cordeiro RA et  al (2013) Minimum inhibitory concentrations of
amphotericin B, azoles and caspofungin against Candida spe-
cies are reduced by farnesol. Med Mycol 51:53–59. doi:10.3109
/13693786.2012.692489
Cugini C, Calfee MW, Farrow JM 3rd, Morales DK, Pesci EC,
Hogan DA (2007) Farnesol, a common sesquiterpene, inhibits
PQS production in Pseudomonas aeruginosa. Mol Microbiol
65:896–906. doi:10.1111/j.1365-2958.2007.05840.x
Cugini C, Morales DK, Hogan DA (2010) Candida albicans-pro-
duced farnesol stimulates Pseudomonas quinolone signal
production in LasR-defective Pseudomonas aeruginosa strains.
Microbiology 156:3096–3107. doi:10.1099/mic.0.037911-0
Davis-Hanna A, Piispanen AE, Stateva LI, Hogan DA (2008) Farnesol
and dodecanol effects on the Candida albicans Ras1-cAMP
signalling pathway and the regulation of morphogenesis. Mol
Microbiol 67:47–62. doi:10.1111/j.1365-2958.2007.06013.x
Deveau A, Piispanen AE, Jackson AA, Hogan DA (2010) Farnesol
induces hydrogen peroxide resistance in Candida albicans yeast
by inhibiting the Ras-cyclic AMP signaling pathway. Eukaryot
Cell 9:569–577. doi:10.1128/EC.00321-09
Dichtl K, Ebel F, Dirr F, Routier FH, Heesemann J, Wagener J (2010)
Farnesol misplaces tip-localized Rho proteins and inhibits cell
wall integrity signalling in Aspergillus fumigatus. Mol Micro-
biol 76:1191–1204. doi:10.1111/j.1365-2958.2010.07170.x
Dixon EF, Hall RA (2015) Noisy neighbourhoods: quorum sensing in
fungal-polymicrobial infections. Cell Microbiol 17:1431–1441.
doi:10.1111/cmi.12490
Du H, Huang G (2016) Environmental pH adaption and morphologi-
cal transitions in Candida albicans. Curr Genet 62:283–286.
doi:10.1007/s00294-015-0540-8
Enjalbert B, Whiteway M (2005) Release from quorum-sensing
molecules triggers hyphal formation during Candida albi-
cans resumption of growth. Eukaryot Cell 4:1203–1210.
doi:10.1128/EC.4.7.1203-1210.2005
Favre-Bonte S, Pache JC, Robert J, Blanc D, Pechere JC, van Delden
C (2002) Detection of Pseudomonas aeruginosa cell-to-cell
signals in lung tissue of cystic fibrosis patients. Microb Pathog
32:143–147. doi:10.1006/mpat.2001.0487
Fuqua WC, Winans SC, Greenberg EP (1994) Quorum sensing in
bacteria: the LuxR-LuxI family of cell density-responsive tran-
scriptional regulators. J Bacteriol 176:269–275
Ganguly S et al (2011) Zap1 control of cell-cell signaling in Candida
albicans biofilms. Eukaryot Cell 10:1448–1454. doi:10.1128/
EC.05196-11
Geisenberger O, Givskov M, Riedel K, Hoiby N, Tummler B, Eberl L
(2000) Production of N-acyl-l-homoserine lactones by P. aer-
uginosa isolates from chronic lung infections associated with
cystic fibrosis. FEMS Microbiol Lett 184:273–278
Ghosh S, Howe N, Volk K, Tati S, Nickerson KW, Petro TM
(2010) Candida albicans cell wall components and farnesol
stimulate the expression of both inflammatory and regu-
latory cytokines in the murine RAW264.7 macrophage
cell line. FEMS Immunol Med Microbiol 60:63–73.
doi:10.1111/j.1574-695X.2010.00717.x
Hall RA et  al (2011) The quorum-sensing molecules farnesol/
homoserine lactone and dodecanol operate via distinct modes
of action in Candida albicans. Eukaryot Cell 10:1034–1042.
doi:10.1128/EC.05060-11
Hawver LA, Jung SA, Ng WL (2016) Specificity and complexity
in bacterial quorum-sensing systems. FEMS Microbiol Rev
40:738–752. doi:10.1093/femsre/fuw014
Hazen KC, Cutler JE (1979) Autoregulation of germ tube formation
by Candida albicans. Infect Immun 24:661–666
Hogan DA (2006) Talking to themselves: autoregulation and quo-
rum sensing in fungi. Eukaryot Cell 5:613–619. doi:10.1128/
EC.5.4.613-619.2006
Hogan DA, Kolter R (2002) Pseudomonas-Candida interactions: an
ecological role for virulence factors. Science 296:2229–2232.
doi:10.1126/science.1070784
Hogan DA, Vik A, Kolter R (2004) A Pseudomonas aer-
uginosa quorum-sensing molecule influences Candida
albicans morphology. Mol Microbiol 54:1212–1223.
doi:10.1111/j.1365-2958.2004.04349.x
Hornby JM et  al (2001) Quorum sensing in the dimorphic fungus
Candida albicans is mediated by farnesol. Appl Environ Micro-
biol 67:2982–2992. doi:10.1128/AEM.67.7.2982-2992.2001
13

Hornby JM, Kebaara BW, Nickerson KW (2003) Farnesol biosyn-
thesis in Candida albicans: cellular response to sterol inhi-
bition by zaragozic acid B. Antimicrob Agents Chemother
47:2366–2369
Jabra-Rizk MA, Meiller TF, James CE, Shirtliff ME (2006) Effect
of farnesol on Staphylococcus aureus biofilm formation and
antimicrobial susceptibility. Antimicrob Agents Chemother
50:1463–1469. doi:10.1128/AAC.50.4.1463-1469.2006
Jensen V et  al (2006) RhlR expression in Pseudomonas aeruginosa
is modulated by the Pseudomonas quinolone signal via PhoB-
dependent and -independent pathways. J Bacteriol 188:8601–
8606. doi:10.1128/JB.01378-06
Jimenez JC, Federle MJ (2014) Quorum sensing in group A Strep-
tococcus Front Cell Infect Microbiol 4:127 doi:10.3389/
fcimb.2014.00127
Joo JH, Jetten AM (2010) Molecular mechanisms involved in
farnesol-induced apoptosis. Cancer Lett 287:123–135.
doi:10.1016/j.canlet.2009.05.015
Jung SA, Chapman CA, Ng WL (2015) Quadruple quorum-sensing
inputs control Vibrio cholerae virulence and maintain system
robustness. PLoS Pathog 11:e1004837. doi:10.1371/journal.
ppat.1004837
Jung SA, Hawver LA, Ng WL (2016) Parallel quorum sensing sign-
aling pathways in Vibrio cholerae. Curr Genet 62:255–260.
doi:10.1007/s00294-015-0532-8
Katragkou A et  al (2015) In  vitro interactions between farnesol and
fluconazole, amphotericin B or micafungin against Candida
albicans biofilms. J Antimicrob Chemother 70:470–478.
doi:10.1093/jac/dku374
Kebaara BW, Langford ML, Navarathna DH, Dumitru R, Nickerson
KW, Atkin AL (2008) Candida albicans Tup1 is involved in
farnesol-mediated inhibition of filamentous-growth induction.
Eukaryot Cell 7:980–987. doi:10.1128/EC.00357-07
Kim J, Sudbery P (2011) Candida albicans, a major human fun-
gal pathogen. J Microbiol 49:171–177. doi:10.1007/
s12275-011-1064-7
Kimura N (2014) Metagenomic approaches to understanding phy-
logenetic diversity in quorum sensing. Virulence 5:433–442.
doi:10.4161/viru.27850
Kruppa M, Krom BP, Chauhan N, Bambach AV, Cihlar RL, Calde-
rone RA (2004) The two-component signal transduction protein
Chk1p regulates quorum sensing in Candida albicans. Eukaryot
Cell 3:1062–1065. doi:10.1128/EC.3.4.1062-1065.2004
Kumamoto CA, Vinces MD (2005) Contributions of hyphae and
hypha-co-regulated genes to Candida albicans virulence. Cell
Microbiol 7:1546–1554. doi:10.1111/j.1462-5822.2005.00616.x
Langford ML, Atkin AL, Nickerson KW (2009) Cellular interactions
of farnesol, a quorum-sensing molecule produced by Can-
dida albicans. Future Microbiol 4:1353–1362. doi:10.2217/
fmb.09.98
Langford ML, Hasim S, Nickerson KW, Atkin AL (2010) Activity
and toxicity of farnesol towards Candida albicans are depend-
ent on growth conditions. Antimicrob Agents Chemother
54:940–942. doi:10.1128/AAC.01214-09
Langford ML et  al (2013) Candida albicans Czf1 and Efg1 coordi-
nate the response to farnesol during quorum sensing, white-
opaque thermal dimorphism, and cell death. Eukaryot Cell
12:1281–1292. doi:10.1128/EC.00311-12
LaSarre B, Federle MJ (2013) Exploiting quorum sensing to con-
fuse bacterial pathogens. Microbiol Mol Biol Rev 77:73–111.
doi:10.1128/MMBR.00046-12
Lee J, Zhang L (2015) The hierarchy quorum sensing network in
Pseudomonas aeruginosa. Protein Cell 6:26–41. doi:10.1007/
s13238-014-0100-x
Leger T, Garcia C, Ounissi M, Lelandais G, Camadro JM (2015)
The metacaspase (Mca1p) has a dual role in farnesol-induced
13
Curr Genet
apoptosis in Candida albicans. Mol Cell Proteomics 14:93–
108. doi:10.1074/mcp.M114.041210
Leonhardt I et  al. (2015) The fungal quorum-sensing molecule
farnesol activates innate immune cells but suppresses cel-
lular adaptive immunity MBio 6:e00143 doi:10.1128/
mBio.00143-15
Lina G et al (1998) Transmembrane topology and histidine protein
kinase activity of AgrC, the agr signal receptor in Staphylo-
coccus aureus. Mol Microbiol 28:655–662
Lindsay AK, Deveau A, Piispanen AE, Hogan DA (2012) Farnesol
and cyclic AMP signaling effects on the hypha-to-yeast tran-
sition in Candida albicans. Eukaryot Cell 11:1219–1225.
doi:10.1128/EC.00144-12
Machida K, Tanaka T (1999) Farnesol-induced generation of reac-
tive oxygen species dependent on mitochondrial transmem-
brane potential hyperpolarization mediated by F(0)F(1)-
ATPase in yeast. FEBS Lett 462:108–112
Martin R et  al (2011) The Candida albicans-specific gene EED1
encodes a key regulator of hyphal extension. PLoS One
6:e18394. doi:10.1371/journal.pone.0018394
McAlester G, O’Gara F, Morrissey JP (2008) Signal-mediated
interactions between Pseudomonas aeruginosa and Can-
dida albicans. J Med Microbiol 57:563–569. doi:10.1099/
jmm.0.47705-0
Mear JB, Kipnis E, Faure E, Dessein R, Schurtz G, Faure K, Guery
B (2013) Candida albicans and Pseudomonas aeruginosa inter-
actions: more than an opportunistic criminal association? Med
Mal Infect 43:146–151. doi:10.1016/j.medmal.2013.02.005
Miller MB, Bassler BL (2001) Quorum sensing in bacteria. Annu Rev
Microbiol 55:165–199. doi:10.1146/annurev.micro.55.1.165
Monnet V, Juillard V, Gardan R (2014) Peptide conversations in
Gram-positive bacteria. Crit Rev Microbiol 42:339–351. doi:10.
3109/1040841X.2014.948804
Morales DK, Jacobs NJ, Rajamani S, Krishnamurthy M, Cubillos-
Ruiz JR, Hogan DA (2010) Antifungal mechanisms by which
a novel Pseudomonas aeruginosa phenazine toxin kills Can-
dida albicans in biofilms. Mol Microbiol 78:1379–1392.
doi:10.1111/j.1365-2958.2010.07414.x
Morales DK, Grahl N, Okegbe C, Dietrich LE, Jacobs NJ, Hogan
DA (2013) Control of Candida albicans metabolism and bio-
film formation by Pseudomonas aeruginosa phenazines MBio
4:e00526–00512 doi:10.1128/mBio.00526-12
Moyes DL et  al (2010) A biphasic innate immune MAPK response
discriminates between the yeast and hyphal forms of Candida
albicans in epithelial cells. Cell Host Microbe 8:225–235.
doi:10.1016/j.chom.2010.08.002
Navarathna DH, Hornby JM, Hoerrmann N, Parkhurst AM, Duhamel
GE, Nickerson KW (2005) Enhanced pathogenicity of Candida
albicans pre-treated with subinhibitory concentrations of flu-
conazole in a mouse model of disseminated candidiasis. J Anti-
microb Chemother 56:1156–1159. doi:10.1093/jac/dki383
Navarathna DH, Hornby JM, Krishnan N, Parkhurst A, Duhamel GE,
Nickerson KW (2007a) Effect of farnesol on a mouse model
of systemic candidiasis, determined by use of a DPP3 knock-
out mutant of Candida albicans. Infect Immun 75:1609–1618.
doi:10.1128/IAI.01182-06
Navarathna DH, Nickerson KW, Duhamel GE, Jerrels TR, Petro TM
(2007b) Exogenous farnesol interferes with the normal pro-
gression of cytokine expression during candidiasis in a mouse
model. Infect Immun 75:4006–4011. doi:10.1128/IAI.00397-07
Nealson KH, Platt T, Hastings JW (1970) Cellular control of the syn-
thesis and activity of the bacterial luminescent system. J Bacte-
riol 104:313–322
Nickerson KW, Atkin AL (2016) Deciphering fungal dimorphism:
farnesol’s unanswered questions. Mol Microbiol. doi:10.1111/
mmi.13601 [Epub ahead of print]
Curr Genet
Nickerson KW, Atkin AL, Hornby JM (2006) Quorum sensing in
dimorphic fungi: farnesol and beyond. Appl Environ Microbiol
72:3805–3813. doi:10.1128/AEM.02765-05
Nickerson K, Atkin A, Hargarten J, Pathirana R, Hasim S (2012)
Thoughts on quorum sensing and fungal dimorphism. In: Wit-
zany G (ed) Biocommunication of Fungi. Springer Netherlands,
Dordrecht, pp 189–204
Niu C, Afre S, Gilbert ES (2006) Subinhibitory concentrations of cin-
namaldehyde interfere with quorum sensing. Lett Appl Micro-
biol 43:489–494. doi:10.1111/j.1472-765X.2006.02001.x
Odds FC (1987) Candida infections: an overview. Crit Rev Microbiol
15:1–5. doi:10.3109/10408418709104444
Parmryd I, Dallner G (1996) Organization of isoprenoid biosynthesis.
Biochem Soc Trans 24:677–682
Pearson JP, Van Delden C, Iglewski BH (1999) Active efflux and dif-
fusion are involved in transport of Pseudomonas aeruginosa
cell-to-cell signals. J Bacteriol 181:1203–1210
Pierce JV, Kumamoto CA (2012) Variation in Candida albicans
EFG1 expression enables host-dependent changes in coloniz-
ing fungal populations MBio 3:e00117–00112 doi:10.1128/
mBio.00117-12
Piispanen AE, Grahl N, Hollomon JM, Hogan DA (2013) Regulated
proteolysis of Candida albicans Ras1 is involved in morpho-
genesis and quorum sensing regulation. Mol Microbiol 89:166–
178. doi:10.1111/mmi.12268
Polke M et al (2016) A functional link between hyphal maintenance
and quorum sensing in Candida albicans. Mol Microbiol.
doi:10.1111/mmi.13526 [Epub ahead of print]
Pollak S, Omer Bendori S, Eldar A (2015) A complex path for
domestication of B. subtilis sociality. Curr Genet 61:493–496.
doi:10.1007/s00294-015-0479-9
Ramage G, Saville SP, Wickes BL, Lopez-Ribot JL (2002) Inhibition
of Candida albicans biofilm formation by farnesol, a quorum-
sensing molecule. Appl Environ Microbiol 68:5459–5463
Roman E, Alonso-Monge R, Gong Q, Li D, Calderone R, Pla J (2009)
The Cek1 MAPK is a short-lived protein regulated by quorum
sensing in the fungal pathogen Candida albicans. FEMS Yeast
Res 9:942–955. doi:10.1111/j.1567-1364.2009.00545.x
Rutherford ST, Bassler BL (2012) Bacterial quorum sensing: its role
in virulence and possibilities for its control Cold Spring Harb
Perspect Med 2
Ryan RP, Dow JM (2011) Communication with a growing family: dif-
fusible signal factor (DSF) signaling in bacteria. Trends Micro-
biol 19:145–152. doi:10.1016/j.tim.2010.12.003
Sappington KJ, Dandekar AA, Oinuma K, Greenberg EP (2011)
Reversible signal binding by the Pseudomonas aeruginosa quo-
rum-sensing signal receptor LasR MBio 2:e00011–00011
Sarkisova SA, Lotlikar SR, Guragain M, Kubat R, Cloud J, Franklin
MJ, Patrauchan MA (2014) A Pseudomonas aeruginosa EF-
hand protein, EfhP (PA4107), modulates stress responses and
virulence at high calcium concentration. PLoS One 9:e98985.
doi:10.1371/journal.pone.0098985
Scheper MA, Shirtliff ME, Meiller TF, Peters BM, Jabra-Rizk MA
(2008) Farnesol, a fungal quorum-sensing molecule triggers
apoptosis in human oral squamous carcinoma cells. Neoplasia
10:954–963
Schramm VL et  al (2008) Transition state analogues in quorum
sensing and SAM recycling. Nucleic Acids Symp Ser (Oxf).
doi:10.1093/nass/nrn038
Scutera S, Zucca M, Savoia D (2014) Novel approaches for the design
and discovery of quorum-sensing inhibitors. Expert Opin Drug
Discov 9:353–366 doi:10.1517/17460441.2014.894974
Sharma R, Jangid K (2014) Fungal Quorum Sensing Inhibitors. In:
Kalia VC (ed) Quorum sensing vs quorum quenching: a battle
with no end in sight. Springer India, New Delhi, pp  237–257.
doi:10.1007/978-81-322-1982-8_20
Shirtliff ME et al (2009a) Farnesol-induced apoptosis in Candida albi-
cans. Antimicrob Agents Chemother 53:2392–2401. doi:10.1128/
AAC.01551-08
Shirtliff ME, Peters BM, Jabra-Rizk MA (2009b) Cross-kingdom inter-
actions: Candida albicans and bacteria. FEMS Microbiol Lett
299:1–8. doi:10.1111/j.1574-6968.2009.01668.x
Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Green-
berg EP (2000) Quorum-sensing signals indicate that cystic fibro-
sis lungs are infected with bacterial biofilms. Nature 407:762–
764. doi:10.1038/35037627
Sudbery PE (2011) Growth of Candida albicans hyphae. Nat Rev
Microbiol 9:737–748. doi:10.1038/nrmicro2636
Sun J, Daniel R, Wagner-Dobler I, Zeng AP (2004) Is autoinducer-2
a universal signal for interspecies communication: a com-
parative genomic and phylogenetic analysis of the synthe-
sis and signal transduction pathways. BMC Evol Biol 4:36.
doi:10.1186/1471-2148-4-36
Swem LR, Swem DL, Wingreen NS, Bassler BL (2008) Deduc-
ing receptor signaling parameters from in  vivo analysis: LuxN/
AI-1 quorum sensing in Vibrio harveyi. Cell 134:461–473.
doi:10.1016/j.cell.2008.06.023
Vuong C, Saenz HL, Gotz F, Otto M (2000) Impact of the agr quorum-
sensing system on adherence to polystyrene in Staphylococcus
aureus. J Infect Dis 182:1688–1693. doi:10.1086/317606
Waters CM, Bassler BL (2005) Quorum sensing: cell-to-cell com-
munication in bacteria. Annu Rev Cell Dev Biol 21:319–346.
doi:10.1146/annurev.cellbio.21.012704.131001
White SJ et  al (2007) Self-regulation of Candida albicans population
size during GI colonization. PLoS Pathog 3:e184. doi:10.1371/
journal.ppat.0030184
Williams P et  al (2000) Quorum sensing and the population-depend-
ent control of virulence. Philos Trans R Soc Lond B Biol Sci
355:667–680. doi:10.1098/rstb.2000.0607
Winstanley C, Fothergill JL (2009) The role of quorum sensing in
chronic cystic fibrosis Pseudomonas aeruginosa infections. FEMS
Microbiol Lett 290:1–9. doi:10.1111/j.1574-6968.2008.01394.x
Yada S, Kamalesh B, Sonwane S, Guptha I, Swetha RK (2015) Quorum
sensing inhibition, relevance to periodontics J Int Oral. Health
(London) 7:67–69
Yang N, Lan L (2016) Pseudomonas aeruginosa Lon and ClpXP pro-
teases: roles in linking carbon catabolite repression system
with quorum-sensing system. Curr Genet 62:1–6. doi:10.1007/
s00294-015-0499-5
Yarwood JM, Bartels DJ, Volper EM, Greenberg EP (2004) Quo-
rum sensing in Staphylococcus aureus biofilms. J Bacteriol
186:1838–1850
Yen CM, Howard DH (1970) Germination of blastospores of Histo-
plasma capslatum. Sabouraudia 8:242–252
Yu LH, Wei X, Ma M, Chen XJ, Xu SB (2012) Possible inhibitory
molecular mechanism of farnesol on the development of flucona-
zole resistance in Candida albicans biofilm. Antimicrob Agents
Chemother 56:770–775. doi:10.1128/AAC.05290-11
Zakikhany K, Naglik JR, Schmidt-Westhausen A, Holland G, Schaller
M, Hube B (2007) In vivo transcript profiling of Candida albicans
identifies a gene essential for interepithelial dissemination. Cell
Microbiol 9:2938–2954. doi:10.1111/j.1462-5822.2007.01009.x
Zhang L, Chang W, Sun B, Groh M, Speicher A, Lou H (2011) Bis-
bibenzyls, a new type of antifungal agent, inhibit morphogenesis
switch and biofilm formation through upregulation of DPP3 in
Candida albicans. PLoS One 6:e28953. doi:10.1371/journal.
pone.0028953
Zhu J et  al (2011) Farnesol-induced apoptosis in Candida albicans is
mediated by Cdr1-p extrusion and depletion of intracellular glu-
tathione. PLoS One 6:e28830. doi:10.1371/journal.pone.0028830
13