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5 Surviving the Storm: How Candida Species Master Adaptation…
obtain energy in a nutritionally starved macrophage environment. The proline catabolism feeds the TCA cycle, generates electron donors, regulates ATP production, and
activates hyphal morphogenesis through the cAMP/PKA pathway, contributing to the
virulence of C. albicans (Silao and Ljungdahl 2021; Silao etal. 2019).
The methionine metabolism, along with the Mup1 transporter, regulates pathogenic traits like lamentation, biolm formation, escape from macrophage, and systemic mice infection. S-adenosylmethionine (SAM) decarboxylates methionine and
yields spermine and spermidine, activating the cAMP/PKA pathway, hence hyphal
induction. Alternatively, CaDUR3 and CaDUR31 are polyamine transporters that
transport spermine, and spermidine in this process also generates ammonia. Hence,
DUR31 is necessary for alkalization, morphogenesis, and hyphal induction. Also,
CaGap4 uptake SAM induces this pathway directly (Kraidlova etal. 2016; Schrevens
etal. 2018). Hence, the methionine pathway regulates the virulence of C. albicans,
making it a crucial nonpreferred nitrogen source.
The intricate regulatory networks governing nitrogen and amino acid metabolism are pivotal contributors to Candida pathogenesis, orchestrating the survival
and virulence of these opportunistic pathogen.
137
5.12 Role ofCarbon Metabolism inCandida Species
Candida spp. have mastered the art of thriving in diverse host environments by efciently harnessing various carbon sources, including fermentable and nonfermentable compounds like lactate, acetate, etc. This adaptability is crucial for their ability
to cause infections in diverse niches, such as the host vagina or gut and survive
within macrophages, where carbon sources exhibit considerable variability (Ene
etal. 2014; Lok etal. 2021). An in-depth understanding of the mechanisms and
regulators governing carbon metabolism in Candida spp. is instrumental in identifying potential therapeutic targets to combat these infections.
5.12.1 Pathways ofCarbon Metabolism
Carbohydrates are the primary carbon source, and glycolysis is engaged in their
breakdown, whilst alternative carbon source utilization involves gluconeogenesis,
the glyoxylate cycle, and fatty acid oxidation.
5.12.1.1 Glycolysis
Glycolysis is the fundamental process through which the preferred carbon source,
glucose, is converted to pyruvate and is essential for respiration and fermentation.
The Snf3 and Rgt2 are involved in the transport of glucose into cells in S. cerevisiae
(Brown etal. 2006; Johnston and Kim 2005). In C. albicans, Hgt4 is its orthologue,
acting as a glucose sensor that regulates hexose transporter genes. The transcription
factors Tye7 and Gal4, in C. albicans, regulate the glycolytic genes unlike GCR1/2
in S. cerevisiae (Askew etal. 2009; Clifton etal. 1978; Uemura and Fraenkel 1990) .
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A. Rana et al.
5.12.1.2 Gluconeogenesis
This process involves the synthesis of glucose from nonfermentable carbon sources
such as lactate and glycerol. In C. albicans, gluconeogenesis, which appears to be
similar to S. cerevisiae, may be involved in delivering carbohydrates for cell wall
formation (Eschrich etal. 2002).
5.12.1.3 Glyoxylate Cycle
The glyoxylate cycle is a modied version of the TCA cycle in which fatty acids or
C2 units such as ethanol or acetate can be used as carbon sources. Isocitrate lyase
(ICL1) and malate synthase (MLS1) are important enzymes found in this cycle and
exhibit high homology between S. cerevisiae and C. glabrata (Chew etal. 2019a;
Dunn etal. 2009).
5.12.1.4 Fatty Acid Oxidation
This cycle involves the breakdown of fatty acids into Acetyl-CoA molecules. These
can subsequently be converted into Carbon dioxide and hexose through the preceding processes, reducing the equivalent from the electron transport chain. While
C. albicans lacks the S. cerevisiae oxidation regulators OAF1 and PIP2, it exhibits
similarities with the lamentous fungus Aspergillus nidulans CTF1 transcription
factors, which control oxidation genes, including the obligatory enzyme FOX2
(Piekarska etal. 2006; Ramirez and Lorenz 2009; Rottensteiner etal. 2003).
5.12.2 Carbon Catabolite Repression (CCR)/Glucose
Repression Pathway
The CCR pathway governs the utilization of favored carbon sources, such as glucose, rather than other carbon sources. In S. cerevisiae, glucose effectively prevents
the use of alternative carbon sources. Whereas C. albicans has exibility in carbon
utilization as its catabolite inactivation at the protein level remains stable even without ubiquitination target sites. The key regulators in Candida albicans include the
serine-threonine kinase SNF1 and its activator Sak1 (SNF1 activating kinase). They,
together with downstream effectors Mig1 and Mig2, govern C. albicans’ alternative
carbon utilization, and their absence reduces C. albicans pathogenicity (Ries etal.
2018; Lagree etal. 2020; Ramirez-Zavala etal. 2017).
5.12.3 Role ofCarbon Metabolism Regulators
inCandida Pathogenesis
Candida sp., such as C. albicans and C. glabrata, heavily depend on a spectrum of
carbon sources like glucose and alternative sources like ethanol, acetate, and lactate
for host colonization and exert their pathogenic potential. The glycolytic pathway is
primarily responsible for sugars processing and is crucial for systemic C. albicans
infections. Mutations affecting glycolysis regulators, such as Tye7 and Gal4, have
5 Surviving the Storm: How Candida Species Master Adaptation…
139
been linked to reduced virulence in infection models like Galleria mellonella and
mice (Askew etal. 2009; Barelle etal. 2006).
When internalized by macrophages, both C. albicans and C. glabrata activate
alternative carbon metabolism pathways, including the glyoxylate pathway, gluconeogenesis, and β-oxidation, due to the glucose-depleted macrophage environment.
Moreover, C. albicans cells grown on alternative carbon sources display increased
resistance to cell wall and osmotic stress, and enhanced resilience against antifungals. Notably, C. albicans cultured in lactate-enriched conditions exhibit heightened
virulence in both systemic and vaginal mouse models. Harassing acetate and lactate
in the gastrointestinal and urogenital tracts provides Candida with supplementary
carbon sources that signicantly boost its pathogenicity and tness within the host
(Lorenz etal. 2004; Lok etal. 2021; Chew etal. 2019b; Rai etal. 2012). Mutation
in glyoxylate cycle enzyme ICL1 observed in both C. albicans and glabrata prevents growth on alternative carbon sources like ethanol, acetate, and oleic acid.
ICL1 is a promising therapeutic target as it is activated during macrophage engulfment and the gene mutants exhibit signicant attenuation in the invasive candidiasis
model (Lorenz etal. 2004; Barelle etal. 2006; Chew etal. 2019b; Rai etal. 2012).
Similarly, mutation in genes FOX2 (β-oxidation functional protein) and FBP1
(fructose- 1,6-biphosphatase) also attenuated virulence in mice models (Ramirez
and Lorenz 2007; Lorenz and Fink 2001). The CCR pathway in C. albicans allows
for utilizing various alternative carbon sources, even in the presence of glucose. The
regulators of this pathway signicantly impact the fungus’s ability to cause infections. Deleting the SNF1 showed that the mutant can grow well under specic conditions. Sak1 controls genes related to alternative carbon metabolism, and its
mutants exhibit different survival abilities in mice. Mutations of downstream regulators Mig1 and Mig2in C. albicans result in defective biolm formation, lament
growth, and more sensitivity to the antifungal drug caspofungin, which affected its
virulence (Lagree etal. 2020; Ramirez-Zavala et al. 2017; Mottola etal. 2020).
Hence, the alternative carbon pathways are crucial for Candida’s ability to cause
infections as the fungus can quickly grow on these carbon sources in the body and
establish itself as a solid commensal and opportunistic pathogen.
5.12.3.1 Role ofMicronutrient Metabolism ofCandida spp.
fortheSurvival andHost Infection
Micronutrients, particularly zinc and iron, are vital for various cellular processes,
including DNA replication and gene regulation and their participation in metal
cofactors within proteins (Waldron etal. 2009; Colvin etal. 2010). Fungal pathogens, when thriving in mammalian hosts, require these trace metals for their survival. To combat this, hosts employ nutritional immunity, manipulating metal
availability to limit pathogen growth either by metal starvation or overdose, effectively acting as a defence against infections (Hood and Skaar 2012).
5.12.3.2 Iron Metabolism
Iron, an indispensable trace element, governs numerous biological functions,
including DNA repair, metabolism, and protein synthesis. The bioavailability of
140
iron is less; hence, the mammalian host cleverly hoards iron through nutritional
immunity, denying fungal pathogens access to it. Haemoglobin and transferrin are
iron storage protein that sequesters iron. Intracellularly, lactoferrin and NRAMP1
store iron, thus denying fungal pathogens access to this vital nutrient. Hence, overcoming iron starvation and maintaining balance is an important pathogenic and
virulent trait of almost all fungal pathogens (Cellier etal. 2007; Nairz etal. 2010;
Devaux and Thiebaut 2019).
A. Rana et al.
5.12.3.3 Candida Iron Transport
In the intricate symbiotic relationship between C. albicans and its host, the fungus
employs three sophisticated iron acquisition and transport strategies. Most of the
knowledge comes from studies in S. cerevisiae.
5.12.3.4 Reductive System
This system involves the conversion of ferric iron into soluble ferrous iron through
the enzymatic activity of plasma membrane-localized ferric reductase enzymes
known as C1 (Fre1) and C95 (Fre10, Rbt2) (Xu etal. 2014; Yu etal. 2014). A
multicopper ferroxidase enzyme called Fet3 (S. cerevisiae) catalyzes the reoxidation of ferrous ions to ferric state through a ferroxidation reaction (Philpott and
Protchenko 2008). Ftr1 is the iron permease protein that transports ferrous ions
(Ziegler etal. 2011).
5.12.3.5 Siderophore Uptake System
While S. cerevisiae, C. albicans, and C. glabrata do not synthesize their siderophores, they possess an impressive ability to capture exogenous siderophores produced by other microbes, a credit to their commensal nature. This is achieved
through the expression of plasma membrane transporters belonging to the Sit1/Arn1
family (Fourie etal. 2018; Bairwa etal. 2017).
5.12.3.6 Haemoglobin-Iron Uptake System
The iron-containing proteins, primarily haemoglobin and other molecules like lactoferrin and transferrin, bound a signicant portion of iron in the human body.
C. albicans, however, has evolved a set of proteins bearing the Common in several
Fungal Extracellular Membrane (CFEM) domains, predominantly Rbt5, Pga7,
Pga10, and Csa2, to exploit these iron sources for its nutritional needs (Fourie etal.
2018; Bairwa etal. 2017; Kuznets etal. 2014).
5.13 Regulation ofIron Homeostasis
Candida sp. are commensal pathogens; hence, they experience entirely different iron
concentrations during gut commensalism and host dissemination. Iron underdose and
overdose are both lethal to living Candida spp.; hence, the regulation of iron homeostasis is crucial in Candida (Kronstad 2013). The Sef1-Sfu1 and HAP43 systems in C. albi-
cans are involved in this regulation. During iron deciency in C. albicans, e.g., systemic
5 Surviving the Storm: How Candida Species Master Adaptation…
141
host infection, leads to the activation of a Cys6Zn2 transcription factor termed Sef1,
which activates HAP43, a CCAAT binding transcription factor (Chen etal. 2011; Baek
etal. 2008). HAP43 is required for growth in iron limited condition (Baek etal. 2008;
Singh etal. 2011). HAP43 also represses Sfu1, a GATA-type transcription factor, which
in iron-replete media physically associates and represses Sef1 and hence indirectly
HAP43 (Chen and Noble 2012). In C. glabrata, iron homeostasis is done through Yap5,
a bZIP transcription factor which binds to YRE motifs of the iron-consuming genes.
Still, this binding is not possible without HAP5 binding to the CCAAT motif. Yap5 harbors truncated Hap4L domain, which has conserved CBC(CCAAT Binding Complex)
sites. Hence, Yap5 interacts with CBC for iron stress response (Thiebaut etal. 2017).
5.13.1 Role ofIron Metabolism Regulators inVirulence
Iron metabolism signicantly impacts the virulence and pathogenicity of Candida
spp., including C. albicans, C. glabrata, and C. auris (Bairwa etal. 2017). Iron availability is limited in the host to prevent pathogen access, and excessive iron catalyzes
ROS formation. Candida efciently exploits host iron, impacting its virulence. For
instance, C. glabrata uses host iron stored in phagolysosomes, interfering with the
type-1 interferon system, leading to iron accumulation in macrophages during infection (Riedelberger etal. 2020a). Mutants of C1 in C. albicans display perturbed
responses, like impaired biolm formation, mitochondrial dysfunction, and reduced
virulence in mice (Yu etal. 2014; Hammacott etal. 2000; Xu etal. 2015). Similarly,
in C. auris, disrupting iron homeostasis with pyrvinium pamoate alters carbon and
lipid metabolism and causes mitochondrial dysfunction (Simm etal. 2022). FTR1
and FET3 orthologs in C. albicans and C. glabrata impact organ colonization, and
FET3 mutant in C. parapsilosis showed altered morphology and biolm formation
(Fang and Wang 2002; Ramanan and Wang 2000; Cheng etal. 2013; Lan etal. 2004;
Srivastava etal. 2014; Chakraborty et al. 2020). However, Pga7 involved in heme
acquisition inuences C. albicans virulence (Kuznets etal. 2014). CBC regulators
like HAP43 in C. albicans and HAP5 in C. parapsilosis contribute to virulence with
defective phenotypes in mouse models (Hsu etal. 2011; Toth et al. 2018). Iron
metabolism also regulates yeast-to-hyphae switching in C. albicans, involving
adhesins like ALS3, and similarly in C. glabrata with EPA1 adhesins, establishing a
link between cell morphology and iron uptake (Bairwa etal. 2017; Almeida etal.
2008; Srivastava etal. 2015). Overall, iron metabolism affects various virulence and
pathogenic traits of Candida spp. and additionally has a variety of pleiotropic defects,
highlighting the importance of iron metabolism in Candida pathogenesis.
5.13.2 Zinc Metabolism
Zinc (Zn2+) is the second essential trace metal after iron and is vital both for humans
and fungal pathogens (Andreini etal. 2009). The zinc element has structural, catalytic,
and regulatory functions in humans (Maret and Li 2009). It is present in the catalytic
142
centre of numerous proteins and regulates multiple cellular signalling networks (Alamir
etal. 2021). Whereas in C. albicans, the proteins like SODs (superoxide dismutase)
and transcription factors like Rim101 and Nrg1 are Zn2+ depended and attenuate virulence. Others like Suc1, involved in sugar metabolism, Cwt1in cell wall remodelling,
and Upc2in ergosterol biosynthesis, all require Zn2+. Hence, access to Zn2+ is essential
for host and Candida spp. survival (Alamir etal. 2021; Staats etal. 2013).
A. Rana et al.
5.13.3 Regulation ofZinc Homeostasis andIts Role
inCandida Pathogenesis
Zinc plays a pivotal role in Candida pathogenicity, with the Zap1 transcription factor
initially studied in S. cerevisiae regulating zinc uptake during zinc scarcity by binding to Zn2+ responsive elements in target genes, including its regulation (Eide 2004).
In C. albicans, Sut1 activates Zap1 (Csr1), triggering the expression of zinc trans-
porters (Zrt2 and Zrt3) and the zincosome importer Zrc1 (Alamir etal. 2021; Soares
etal. 2020). Zrt1 is expressed under neutral/alkaline conditions and relies on Pra1
expressed during host cell invasion, and they both transport Zn2+ into the cytoplasm
(Citiulo etal. 2012). In acidic and alkaline environments, Zrt2 functions as a zinc
transporter (Crawford etal. 2018). Zinc, once in the cytoplasm, is transported to the
nucleus, ER, and vacuole by specic transporters like Zrt3 (on vacuoles). In contrast,
Zrc1 (a CDF family transporter in the vacuole) manages zinc detoxication and storage (Crawford et al. 2018; Bird and Wilson 2020; MacDiarmid et al. 2003).
Disruptions in zinc metabolism, as seen in Zap1 mutants of C. albicans, result in
diminished lamentation, altered biolm formation, defective hyphae formation, and
reduced immunityin vivo mice model (Xu etal. 2015; Kim etal. 2008; Nobile etal.
2009; Bottcher etal. 2015). Similarly, Sut1 mutants also exhibit impaired invitro
survival, a decit compensated by ZAP1 overexpression (Xu etal. 2015). In C. dub-
liniensis, the csr1∆/∆ shows reduced virulence in the embryonated chicken egg
model (Bottcher etal. 2015). Zinc dysregulation leads to high levels of reactive oxygen species (ROS) and affects virulence factors like superoxide dismutase (SODs)
and metalloproteases (Staats etal. 2013). Though the deletion of specic zinc transporters like Zrt1,2 and Zrc1 did not affect survival in the Galleria mellonella model
in C. parapsilosis, it suggested the potential use of zinc-based poisoning by macro-
phages to eliminate the pathogen (Bottcher etal. 2015). In the phagosomally trapped
C. glabrata, zinc is transported via zinc transporters with metallothionein acting as
zinc chaperons causing zinc toxicity (Riedelberger etal. 2020b).
5.14 Conclusions andFuture Perspective
Candida infections are a growing concern in the healthcare sector, primarily due
to the emergence of drug-resistant strains, particularly non-albicans Candida spp.
While Candida, including the common C. albicans, is often harmless in healthy
individuals, it can seriously threaten those with compromised immune systems.
5 Surviving the Storm: How Candida Species Master Adaptation…
143
The escalation of resistance to antifungal drugs like azoles and echinocandins is a
signicant issue, as these drugs are the primary treatment options for invasive
candidiasis. In particular, strains such as C. glabrata and C. auris have gained
notoriety for their extreme drug resistance, rendering traditional antifungals less
effective. This scenario is becoming more complex due to the increasing population of individuals with compromised immune systems, poor drug efcacy, and
associated host toxicity. These things will overburden healthcare facilities; moreover, there is a looming vulnerability of Candida infection outbreaks. One promising strategy is to target various factors that make Candida virulent, such as
biolm formation, phospholipase activity, and adhesin production. These virulent
factors are crucial in the pathogen’s ability to inltrate, persist within, and disseminate throughout the host. By gaining a deeper understanding of these virulence traits’ molecular and metabolic regulation, it may be possible to develop
interventions that can prevent their production. This could disrupt the interaction
between the host and Candida, potentially leading to the creation of more effective therapeutics. This approach should extend beyond C. albicans to encompass
lesser known but equally or more potent non-albicans Candida sp. like C. gla-
brata, C. auris, and C. parapsilosis. These efforts could broaden the library of
effective compounds against Candida infections and reduce selective pressure on
currently limited antifungal drugs (Arendrup and Patterson 2017; Taei etal. 2019;
Ahmad Khan etal. 2020).
This chapter explores a great diversity of virulence factors utilized by Candida
species for host interaction. Candida species has a diverse array of virulent factors
that regulate its morphology, adhesion, and arsenal of enzymes, including candidalysin, which aids host barrier degradation. Candida spp. also possess a multitude of regulators that enable them to sense and adapt to changes in pH and
temperature, maintaining the optimal conditions for various proteins crucial to
their survival. Successfully colonizing nutritionally starved host niches, like the
vaginal and gastrointestinal linings and host phagosomes, demands remarkable
metabolic adaptation. Candida spp. metabolic exibility and the factor it employs
to secure various macro nutrients and micronutrients are explored within this
review. Additionally, the intricate network of signalling pathways and gene regulators that govern these virulent factors are discussed. Notably, the absence of
specic elements in different infectious traits renders Candida spp. avirulent invitro or invivo settings, underscoring their pivotal role in Candida pathogenicity.
The future of fungal therapeutics hinges on our ability to characterize and
target these factors, both already known and undiscovered or underexplored but
possessing distinct roles in Candida’s pathogenesis. Achieving this milestone in
fungal therapeutics necessitates a comprehensive understanding of these factors
and taking them to clinical trials. Furthermore, in our pursuit of combating
drug-resistant candidiasis, we must pay equal attention to NCAS as they rapidly
develop resistance. Continual progress in unravelling the signicance of these
virulent traits holds the key to overcoming the challenges posed by drugresistant candidiasis.
144
A. Rana et al.
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