REVIEW

published: 12 December 2018

doi: 10.3389/fmicb.2018.03081

Candida auris: What Have We

Learned About Its Mechanisms of
Pathogenicity?
Luana Rossato and Arnaldo Lopes Colombo*
Special Mycology Laboratory, Universidade Federal de São Paulo, São Paulo, Brazil

Candida auris has emerged globally as a multidrug-resistant (MDR) medical care-

associated fungal pathogen. Recent reports have demonstrated that C. auris usually
expresses fewer virulence factors than does Candida albicans. However, the tendency
of C. auris transmission within and between healthcare facilities is unique among
Candida spp. and is possibly promoted by virulence and pathogenicity factors that
facilitate skin colonization and environmental persistence. To understand the ability of
this yeast to cause disease, we herein discuss several virulence and pathogenicity
aspects of C. auris.
Keywords: Candida auris, pathogenicity, virulence, genomics, phenotypic traits, thermic and osmotic stress,
biofilms
Edited by:
Sascha Brunke,
Leibniz Institute for Natural Product
Research and Infection Biology,
INTRODUCTION
Germany
Candida auris is an emerging multidrug-resistant (MDR) yeast pathogen that causes healthcare-
Reviewed by: associated invasive infections. There is growing evidence suggesting that C. auris may persistently
Darius Armstrong-James,
colonize the hospital environment and multiple body sites of patients, leading to high
Imperial College London,
United Kingdom
transmissibility, and prolonged outbreaks (Schelenz et al., 2016; Vallabhaneni et al., 2017). Indeed,
Arianna Tavanti, we are encountering for the first time an MDR yeast pathogen with a high capacity to cause
University of Pisa, Italy clusters of invasive infections in medical centers around the world (Kim et al., 2009; Lee et al.,
*Correspondence: 2011; Chowdhary et al., 2013, 2014; Calvo et al., 2016; Prakash et al., 2016; Lockhart et al., 2017;
Arnaldo Lopes Colombo Morales-Lopez et al., 2017). C. auris fungemia results in crude mortality rates ranging from 32 to
arnaldolcolombo@gmail.com 66%, depending on the patient’s underlying conditions, geographic region, and age as well as the
clinical management of the infection (Lee et al., 2011; Sarma et al., 2013; Chowdhary et al., 2014;
Specialty section: Calvo et al., 2016; Schelenz et al., 2016; Morales-Lopez et al., 2017; Vallabhaneni et al., 2017).The
This article was submitted to description of C. auris fungemia outbreaks worldwide illustrates the dramatically increased need
Infectious Diseases,
to develop new strategies to prevent and control infections due to this multiresistant pathogen.
a section of the journal
Frontiers in Microbiology
Despite the large number of papers addressing C. auris infections published since 2009, few have
attempted to investigate the pathogenicity and virulence of this new human pathogen. Here, we
Received: 06 August 2018
review all papers addressing biological factors that affect the pathogenicity of C. auris.
Accepted: 29 November 2018
Published: 12 December 2018
Citation: WHAT WE HAVE LEARNED FROM COMPARATIVE GENOMICS
Rossato L and Colombo AL
(2018) Candida auris: What Have We
OF C. auris?
Learned About Its Mechanisms
of Pathogenicity? C. auris was first described after it was isolated from the ear canal of a 70-year-old Japanese
Front. Microbiol. 9:3081. woman at Tokyo Metropolitan Geriatric Hospital in Japan (Satoh et al., 2009). After this report, a
doi: 10.3389/fmicb.2018.03081 retrospective review of Candida strain collections revealed that the earliest known strain of C. auris

Frontiers in Microbiology | www.frontiersin.org 1 December 2018 | Volume 9 | Article 3081

Rossato and Colombo Virulence of Candida auris

dates back to 1996 in South Korea (Kim et al., 2009). However, pseudohyphae-like forms under high-salt stress (Wang et al.,
it is unknown why C. auris has only recently emerged in a 2018) and, occasionally, in the biofilm community (Sherry et al.,
wide variety of locations. Based on whole genome sequencing 2017).Pseudohyphae-like forms are characterized by rudimentary
(WGS), four different clades of C. auris have been described by growth, with an elongated shape and incomplete cell division
region (East Asian, South Asian, African, and South American). (Sherry et al., 2017; Wang et al., 2018). Indeed, comparative
Moreover, analyses of SNPs identified by WGS and multilocus genome analyses have confirmed that C. auris and closely related
sequence typing (MLST) have shown low genetic diversity species do not have two genes, candidalysin (ECE1) and hyphal
between isolates within each C. auris clade. These results cell wall protein (HWP1), both of which are highly expressed in
indicate a high degree of clonality within clades and suggest C. albicans and the transcription of both is strongly associated
the independent, nearly simultaneous emergence of the four with hyphal formation (Munoz et al., 2018).
populations on three continents (Lockhart et al., 2017). In this scenario, C. auris fails to form chlamydospores after
The complete genome of C. auris was only recently growth on cornmeal agar when incubated for 3 days at 30◦ C
investigated (Chatterjee et al., 2015; Sharma et al., 2015, 2016), and does not germinate when incubated with fetal bovine serum
and we are far from fully understanding of the role of different (FBS). This fact was confirmed in the Galleria mellonella model
genes in the pathogenicity and virulence of this emerging of infection of C. auris, during which the isolates did not undergo
pathogen. The main problem is that the C. auris genome significant filamentation at 18 h or at any time post infection
sequence contains many uncharacterized and hypothetical (Borman et al., 2016).
proteins, and it is unclear whether these proteins are involved Growth curve analyses for C. auris and C. albicans isolates
in species-specific characteristics that promote its aggressiveness demonstrate that the two Candida species have similar growth
as a pathogen (Chatterjee et al., 2015). C. auris is closely related patterns, reaching the stationary phase within approximately
to three other rare Candida species – Candida haemulonii, 20 h (Larkin et al., 2017). An interesting observation regarding
Candida duobushaemulonii, and Candida pseudohaemulonii – the growth of C. auris is that certain isolates grow in clumps
in the family Metschnikowiaceae, along with more common (i.e., budding occurs, but daughter cells are not released), which
Candida lusitaniae (Cendejas-Bueno et al., 2012). results in large aggregates of organisms that cannot be easily
Initial analyses of the C. auris genome suggest that 40% disrupted in vitro (Borman et al., 2016). These isolates are
of C. auris proteins are orthologous to those of C. lusitaniae called “aggregate” strains, and certain aggregate strains are too
(Sharma et al., 2016). Considering the limited susceptibility large for G. mellonella larval inoculation, hindering accurate
of C. lusitaniae to amphotericin B and C. haemulonii to yeast cell counting. To overcome this limitation, homogeneous
amphotericin B and azoles (Kim et al., 2009; Espinel-Ingroff et al., inoculum preparations have been obtained after allowing the
2017), this orthology suggests that C. auris shares some genetic initial suspension of fungal cells to settle for 10 min followed
characteristics with both species that may have helped it become by removal of the supernatant containing individual yeast
resistant to multiple antifungal drugs. Indeed, a significant cells for infecting larvae (Borman et al., 2016). Based on
portion of the C. auris genome encodes transporter genes and this protocol, it was possible to compare the pathogenicity of
protein kinases, such as the ABC and MFS transporter families, aggregating and non-aggregating strains of C. auris with other
and a number of zinc cluster transcription factor orthologs such yeast species. The results demonstrated strain-specific variability
as TAC1 (29% similarity with Candida albicans), which may in behavior, with the aggregate-forming isolates of C. auris
facilitate acquisition of drug resistance (Sharma et al., 2016). exhibiting significantly reduced pathogenicity compared to their
By comparing the C. auris genome with that of C. albicans non-aggregating counterparts (Borman et al., 2016). Moreover,
that is well annotated and well-studied we may suggest that when infected G. mellonella larvae were dissected, large numbers
C. auris genome harbors genes that are well-characterized as of individual budding yeast cells of non-aggregating strains
virulence factors in other Candida species, including genes for of C. auris were found inside phagocytes. In addition, the
biofilm formation, proteinases, lipases, phospholipases, adhesins, larvae inoculated with individual yeast cells prepared from
secreted aspartyl proteases and transporters belonging to the aggregate-forming strains of C. auris exhibited large aggregates of
ABC and major facilitator superfamily (MDR transcription C. auris cells, with few individual yeast cells, indicating that the
factors) which are involved with azole resistance (Chatterjee et al., ability to produce large aggregates had been maintained in vivo
2015). (Borman et al., 2016). Yeast cell aggregates were also observed
in the kidneys of mice infected with C. auris, suggesting that
aggregation might be a mode of immune evasion and persistence
PHENOTYPIC TRAITS AND in tissues, which warrants further investigation (Ben-Ami et al.,
IMPLICATIONS FOR PATHOGENICITY 2017).

Phenotypic switching and morphogenesis are well-known

virulence attributes of C. albicans (Polke et al., 2015). Although TOLERANCE TO THERMIC AND
micromorphological studies of C. auris colonies suggest that OSMOTIC STRESSES
this pathogen does not produce germ tubes, pseudohyphae
or chlamydospores (Lee et al., 2011; Chowdhary et al., 2014; Survival and growth at physiologic temperature are
Borman et al., 2016; Wang et al., 2018), this yeast may present prerequisites for microbial invasion and pathogenicity.

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Rossato and Colombo Virulence of Candida auris

C. auris exhibits thermotolerance, growing optimally at C. auris AND ITS ALARMING ABILITY TO
37◦ C and maintaining viability up to 42◦ C. In addition, PERSISTENTLY COLONIZE HUMAN
this pathogen is salt tolerant, and cells aggregate into large,
difficult-to-disperse clusters, which may promote persistence HOST AND THE ENVIRONMENT
in the hospital environment (Satoh et al., 2009; Borman et al.,
Studies have demonstrated the ability of C. auris to colonize
2016).
and spread throughout hospital environments. One of the most
The ability of C. auris isolates to grow at 37◦ C and 40◦ C
alarming characteristics of C. auris is the ability of this yeast
appears to be similar to that of C. albicans, and certain isolates
to adhere to and persist on abiotic surfaces, including dry and
also grow at 42◦ C (Ben-Ami et al., 2017). Other authors have
moist surfaces, bedding material, floors, sinks and beds, as well
confirmed that C. auris can grow at high temperature (40◦ C)
as human skin, ears, and nasal cavities (Schelenz et al., 2016;
and salinity (10%wt/vol) when cultured in Sabouraud (SAB) or
Piedrahita et al., 2017; Vallabhaneni et al., 2017; Welsh et al.,
yeast nitrogen base (YNB) broth with dulcitol or mannitol as the
2017). In one study, the survival of eight C. auris isolates
carbon source (Welsh et al., 2017).
was compared with other Candida species on dry or moist
Wang et al. (2018) examined the morphology of C.
surfaces for up to 7 days, with the recovery of C. auris being
auris on the rich media YPD and YPD plus 10% NaCl,
similar to that of other Candida species, vancomycin-resistant
with a round appearance on the former medium but an
Enterococcus (VRE), methicillin-resistant Staphylococcus aureus
elongated shape on the latter. Interestingly, a small portion
(MRSA), and carbapenem-resistant Enterobacteriaceae (CRE)
of highly elongated and pseudohyphae-like forms were
(Piedrahita et al., 2017).
observed when grown on YPD plus 10% NaCl (Wang
Moreover, the capacity of C. auris to persist and colonize
et al., 2018). These results suggest that high-salt stress may
the plastic surfaces of medical devices was compared with
result in incomplete cell division, leading to the formation of
that of Candida parapsilosis (Welsh et al., 2017) using two
pseudohyphae-like forms. So far, the molecular mechanism
complementary independent methods: culture [as measured by
related to this phenotype of C. auris has not yet been
colony-forming units (CFU)] and solid-phase cytometry (which
investigated.
detects viability, as measured by esterase activity) (Smith et al.,
2010). For CFU determination, C. auris and C. parapsilosis
suspensions of 5 × 106 cells per mL were applied to dried plastic
IMPORTANCE OF LYTIC ENZYMES FOR surfaces and followed to grow for up to 28 days. C. auris and
FUNGAL INVASIVENESS C. parapsilosis were viable for at least 14 and 28 days, respectively;
however, viable C. auris was detected for longer periods than
The production of phospholipases and proteinases has been
previously observed by quantitative culturing. When solid-phase
recognized as relevant for Candida pathogenicity in the human
cytometry was used to assess individual cells for viability for
host, helping in the adherence to and invasion of host cells
longer periods of time, the results indicated that the cells entered
(Polke et al., 2015). Hydrolases are the largest group of
into a viable non-culturable state, and more viable C. auris than
enzymes (42%) found in the C. auris (strain 6684) genome,
C. parapsilosis cells were detected at all time points (Welsh et al.,
followed by transferases (25%) and oxidoreductases (19%)
2017).Overall, the adherence of C. auris to medical devices may
(Chatterjee et al., 2015). Furthermore, comparative genome
play a role in the development of catheter-related fungemia. In
analyses have revealed similar numbers of lipases in the C. auris
contrast to C. albicans, C. auris exhibits minimal ability to adhere
relative to those of C. albicans and C. dubliniensis (Munoz
to silicone elastomer (Larkin et al., 2017).
et al., 2018). The ability to produce lytic enzymes has been
demonstrated in C. auris isolates, and the production of these
enzymes is strain dependent (Kumar et al., 2015; Larkin et al.,
2017). BIOFILM PRODUCTION AND IMPACT ON
An in vitro study evaluating C. auris isolates from different ANTIFUNGAL RESISTANCE
geographical regions showed that 37.5% of the tested strains
(6/16 isolates) exhibited phospholipase activity and that 64% Biofilms are a common form of microbial growth that are crucial
(9/14 isolates) were positive for proteinase (Larkin et al., 2017). for the development of a broad spectrum of infections in the
Similarly, most strains displayed hemolysin activity, conferring human host and also for defending pathogens from phagocytes
a high capacity for iron acquisition, growth, and invasiveness and antimicrobial drugs (Fanning and Mitchell, 2012). Seven
leading to widespread infection (Tsang et al., 2007; Kumar et al., highly conserved genes (PLB3, IFF4, PGA52, PGA26, CSA1,
2015). HYR3, and PGA7) are upregulated during biofilm production
In fact, a recent study conducted by Wang et al. (2018) across isolates representative of C. auris, C. haemulonii,
demonstrated that the level of aspartyl proteinase (Saps) secreted C. duobushaemulonii, and C. pseudohaemulonii. The same
by C. auris isolate at 42◦ C was higher than that exhibited by proteins are associated with biofilm production and mechanisms
C. albicans at the same temperature (Wang et al., 2018). These of antifungal resistance in C. albicans strains (Kean et al., 2018).
findings suggest that C. auris isolates are not only well adapted to As documented with other Candida species (Hirakawa et al.,
temperature stress but also maintain their pathogenicity at higher 2015), there is a large intra-specific variation in the capacity of
temperatures. biofilm production by C. auris. Initial investigation with fifteen

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Rossato and Colombo Virulence of Candida auris

C. auris isolates cultured from ear specimens failed to detect any C. auris were injected via the tail vein, with all animals infected
biofilm production (Oh et al., 2011). Later, Larkin et al. (2017) with C. albicans dying by the 6th day post-infection but no animal
performed a comparative study to assess biofilm production infected with C. auris dying during the same period (Wang et al.,
by two isolates of C. auris and one isolate of C. albicans 2018).
using silicone elastomer as a substrate. Quantification of the Due to economic and especially ethical issues, the scientific
biofilms was performed using a colorimetric metabolic assay (to community has in the last decade limited the use of mammalian
measure mitochondrial dehydrogenase activity-XTT) and dry infection models to study the virulome of fungi (Krappmann,
weight analysis (to measure total biofilm mass). During this assay, 2015). Driven by the need for validating alternative models to
the authors were able to detect C. auris biofilm production that replace mammalian systems, invertebrate organisms, such as
was composed of yeast cells adhering to the catheter material. In G. mellonella and C. elegans, have been extensively used as mini-
contrast, the C. albicans biofilm presented a highly heterogeneous hosts for studying the virulence attributes and host response of
architecture composed of yeast cells and hyphae embedded Candida infections (Cotter et al., 2000).
within the extracellular matrix. Moreover, the C. auris biofilms, Within this context, Borman et al. (2016) developed a model
unlike the C. albicans biofilms, displayed a limited amount of of G. mellonella fungal infection using an inoculum solution
extracellular matrix (Larkin et al., 2017). of 1 × 106 yeast cells of C. auris, C. albicans and Candida
Recently, a comparative study was performed to evaluate the tropicalis isolates, whereby it was possible to demonstrate that
production of biofilm by isolates of C. albicans, Candida glabrata, C. albicans and C. tropicalis exhibit significantly higher virulence
two non-aggregating strains of C. auris and two aggregating in terms of the kinetics of larval death and number of larvae killed
strains of C. auris. The authors used 96-well polystyrene (Borman et al., 2016). In accordance with other publications,
microtiter plates and measured total fungal biomass using a these researchers found that C. auris isolates were not able to
crystal violet assay. The results showed the greatest biofilm mass develop significant pseudohyphae into tissues of infected larvae
for C. albicans, followed by C. auris and C. glabrata. The C. auris (Lee et al., 2011; Chowdhary et al., 2013; Kathuria et al., 2015;
biofilm was predominately composed of budding yeasts and Borman et al., 2016). Wang et al. (2018) also confirmed that the
occasional pseudohyphae (Sherry et al., 2017). In the same study, Chinese C. auris strain exhibits reduced virulence in G. mellonella
the susceptibility of C. auris biofilms to drugs was assessed, with larva compared to a C. albicans isolate. Overall, compared to
micafungin and caspofungin being ineffective against biofilms C. glabrata, C. auris strains are usually more virulent in animal
“in vitro” and requiring > 32 mg/L to inhibit sessile cells (Sherry models.
et al., 2017). Investigation of the immune response to C. auris using the
Zebrafish model of invasive candidiasis revealed a recruitment
of approximately 50% less neutrophils in response to C. auris
VIRULENCE OF C. auris IN ANIMAL infection when compared to C. albicans (Johnson et al., 2018).
MODELS Moreover, in vitro human neutrophils were co-cultured with
Candida cells (2 × 107 cells) for 4 h and fungal viability was
A comparative study of virulence exhibited by C. auris measured. Neutrophils inhibited C. albicans growth by 75%; in
and C. haemulonii isolates was performed in a mouse contrast, the burden of C. auris was not impacted replicating
model of hematogenous-disseminated candidiasis after beyond the initial inoculums, showing very little killing of C. auris
immunosuppression with cyclophosphamide (150 mg/kg by neutrophils. Using fluorescence microscopy, they analyzed
intraperitoneally). The C. haemulonii isolates were found to neutrophil-Candida interactions, and at 1 h, very few neutrophils
be completely non-virulent, with 100% of the mice surviving (15%) were either engulfing or adherent to co-incubated C. auris
at 12 days after inoculation and no visible signs of illness. In cells. In contrast, 50% of neutrophils exhibited some activity
contrast, inoculation with C. auris resulted in rapid death, against C. albicans. These findings suggest that neutrophils
with only 20% survival at 5 days after infection (Munoz et al., are more able to engage and kill C. albicans over C. auris
2018). Another comparative study of Candida spp. virulence isolates (Johnson et al., 2018). Viability of neutrophils co-cultured
using an immunocompetent murine model of disseminated with C. albicans decreased by half, while upon exposure to
infection showed high virulence of C. albicans isolates, followed C. auris, almost all neutrophils remained viable. The production
by C. auris, C. glabrata, and C. haemulonii (Fakhim et al., of neutrophils extracellular traps (NETs) in response to C. auris
2018). In this study, the animals were challenged with 105 exposition was measured by scanning electron microscopy.
CFU/mouse injected into the lateral tail vein, and death rates It was found that neutrophils engaging in phagocytosis or
were recorded up to 30 days post-infection. Mice infected with releasing NETs were rarely observed after exposition to C. auris.
C. albicans exhibited 20% survival, with a median survival time Furthermore, quantifying NET formation showed that C. auris
(MST) of 13 days, where as mice infected with C. auris showed did not trigger free DNA release, consistent with the lack of NET
30–40% survival until the end of the experiment, with an MST of production observed in microscopy experiments (Johnson et al.,
16–17 days post-infection (Fakhim et al., 2018). 2018).
The virulence of a single C. auris isolate obtained from a Taking together data provided by experimental models using
Chinese fungemic patient was recently evaluated in a mouse mice and invertebrate animals, we may conclude that C. auris is
model of Candida systemic infection. Inoculum preparations of certainly less virulent than is C. albicans. Nonetheless, C. auris is
1 × 106 CFU/ml of C. albicans (SC5314) and 1 × 107 CFU/ml significantly more virulent than are C. glabrata and C. haemulonii

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Rossato and Colombo Virulence of Candida auris

(Fakhim et al., 2018) and other species of Candida also considered representative of biological properties exhibited by a few clonal
to be resistant to multiple drugs. Indeed, C. auris was able to strains.
induce systemic infection and mortality rates higher than 50% in An additional point that deserves more attention is the
2 of 3 studies investigating its virulence in a mouse model (Ben- characterization of adhesins and other molecules responsible for
Ami et al., 2017; Fakhim et al., 2018; Wang et al., 2018). Despite the capability of C. auris to persistently colonize abiotic and biotic
limited virulence when compared to C. albicans, in vitro assays surfaces. Indeed, this pathogen is able to survive and persist under
conducted with human neutrophils showed that C. auris is less different environmental conditions, including on dry materials,
effective than C. albicans in triggering neutrophils engulfment bedding material, floors, sinks and beds, and it exhibits tolerance
and NET production. to temperature and osmotic stresses (Ben-Ami et al., 2017; Welsh
et al., 2017).
In summary, our review shows that C. auris expresses several
FINAL COMMENTS AND FUTURE virulence traits including genes that are well-characterized in
DIRECTIONS other Candida species, including genes for biofilm formation,
proteinases, lipases, phospholipases, adhesins, secreted aspartyl
Although animal studies indicate that C. auris has reduced proteases, and transporters which are involved with azole
pathogenicity and virulence compared to C. albicans, this resistance. Despite exhibiting less virulence than C. albicans
emerging pathogen appears to be far more able to induce isolates, recent findings suggest that C. auris fails to activate the
systemic infection and mortality than other potential MDR yeast innate immune response and production of NETs by human
pathogens, such as C. glabrata and C. haemulonii (Fakhim et al., neutrophils, what certainly may play a role in the high mortality
2018). This finding is likely to be related to the tolerance of associated to this infection.
C. auris strains to osmotic and high-temperature stress as well
as to its ability to produce several lytic enzymes and biofilm
(Ben-Ami et al., 2017; Welsh et al., 2017). AUTHOR CONTRIBUTIONS
The complete genome sequence of C. auris is available
(Chatterjee et al., 2015; Sharma et al., 2015; Lockhart et al., LR and AC contributed equally in the paper. Both wrote the
2017), and it is currently possible to design experiments to manuscript and performed all the necessary literature searches
better characterize the molecular mechanisms responsible for and data compilation.
the capability of this pathogen to readily become resistant
to multiple antifungal drugs and to determine the presence
of genes related to pathogenicity and virulence factors. An FUNDING
important limitation of virulence analyses based on clonal strains
cultured from patients during outbreaks is that it remains This paper was supported by the following grant(s): Fundação de
unclear whether such findings may be safely extrapolated Amparo à Pesquisa do Estado de São Paulo 2017/19095-2 and
to all isolates of the species or whether they are only 2017/02203-7.

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(2016). Evidence of genotypic diversity among Candida auris isolates by author(s) and the copyright owner(s) are credited and that the original publication
multilocus sequence typing, matrix-assisted laser desorption ionization time- in this journal is cited, in accordance with accepted academic practice. No use,
of-flight mass spectrometry and amplified fragment length polymorphism. distribution or reproduction is permitted which does not comply with these terms.

Frontiers in Microbiology | www.frontiersin.org 6 December 2018 | Volume 9 | Article 3081