MINIREVIEW
Sexual reproduction and dimorphism in the pathogenic
basidiomycetes
Carl A. Morrow & James A. Fraser
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
Correspondence: James A. Fraser, School of
Chemistry and Molecular Biosciences, 358
Molecular Biosciences Building, Cooper Road,
The University of Queensland, Brisbane, QLD
4072, Australia. Tel.: 161 7 3365 4868; fax:
161 7 3365 4273; e-mail:
[email protected]
Received 8 June 2008; revised 12 November
2008; accepted 17 November 2008.
First published online January 2009.
DOI:10.1111/j.1567-1364.2008.00475.x
Abstract
Many fungi in the Basidiomycota have a dimorphic life cycle, where a monokaryotic yeast form alternates with a dikaryotic hyphal form. Most of the
dimorphic basidiomycetes are pathogenic on plants, animals or other fungi. In
these species, infection of a host appears to be closely linked to both dimorphism
and the process of sexual reproduction. Sex in fungi is governed by a specialized
region of the genome known as the mating type locus that confers cell-type
identity and regulates progression through the sexual cycle. Here we investigate
sexual reproduction and lifestyle in emerging human pathogenic yeasts and plant
pathogenic smuts of the Basidiomycota and examine the relationship among sex,
dimorphism and pathogenesis.
Editor: Teun Boekhout
Keywords
Basidiomycota ; yeast; mating; sexual
reproduction; pathogenesis.
Introduction
With over 80 000 described species, the ubiquitous Fungi are
a spectacularly successful kingdom. While most are saprobes
that decay organic matter, symbionts of plants or harmless
commensals, the pathogenic species are of particular interest: an estimated 32% of fungi are plant pathogens, while
only c. 0.5% (roughly 400 species) are clinically relevant
human pathogens (Shivas & Hyde, 1997; De Hoog, 2000;
Hawksworth, 2001; Kirk et al., 2001). The phylum Ascomycota includes the majority of described fungi, and represents
most of the plant pathogens and c. 90% (c. 350) of human
pathogenic fungi (Hawksworth, 2001; Mitchell, 2005). Their
sister phylum is the Basidiomycota, which numbers an
estimated 30 000 species. While the saprobic mushrooms
are the largest clade, a significant number of basidiomycetes
are pathogenic: the rusts and smuts number about 7000 and
1400 species, respectively, and a further 40 yeast species have
been reported to infect humans and animals (Kirk et al.,
2001; Mitchell, 2005).
The Basidiomycota are divided into three subphyla (Table 1).
The Agaricomycotina contain the majority of described
basidiomycete species (c. 20 000), including the mushroom
FEMS Yeast Res 9 (2009) 161–177
fungi, the jelly fungi and a variety of yeasts (Hibbett, 2006).
The Ustilaginomycotina (c. 1500) comprise the majority
of the smut fungi plus some dimorphic pathogens, while
the Pucciniomycotina (4 8000 species) comprise mainly
the obligately plant pathogenic rust fungi plus an array of
parasites and saprotrophs (Aime et al., 2006; Begerow et al.,
2006; Hibbett et al., 2007).
A variety of fungi in the Basidiomycota have a single-celled
growth form called a yeast, which is derived from the
budding of a meiospore (basidiospore). The yeast growth
form is a rounded or an elongated cell that reproduces
asexually by budding, fission or production of forcefully
ejected ballistoconidia (Flegel, 1977; Fell et al., 2001). Yeast
states are widespread across the three subphyla, and the term
bears no taxonomic implication. Species that alternate
between a single-celled yeast form and a filamentous growth
form are termed ‘dimorphic’, in contrast to ‘monomorphic’
species that have only one known growth form (Fell et al.,
2001). The filamentous form consists of long, branching
tubular cells known as hyphae, which are divided into
compartments by septa and grow at the apical cell (Steinberg,
2007). Dimorphic species are common in the three subphyla
of the Basidiomycota, where the unicellular yeast phase is
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162
C.A. Morrow & J.A. Fraser
Table 1. Classification of selected pathogenic basidiomycete genera
Subphylum
Class
Agaricomycotina
Agaricomycetes
Dacrymycetes
Tremellomycetes
Ustilaginomycotina Exobasidiomycetes
Ustilaginomycetes
Genus
Sexuality
Cryptococcus/
Filobasidiella
Trichosporon
Bipolar or
asexual
Asexual
Ustilago
Bipolar or
tetrapolar
Bipolar or
tetrapolar
Bipolar or
asexual
Sporisorium
Incertae sedis
Pucciniomycotina
Malassezia
Pucciniomycetes
Agaricostilbomycetes
Cystobasidiomycetes Rhodotorula
Microbotryomycetes Microbotryum
Sporobolomyces/
Sporidiobolus
Rhodotorula/
Rhodosporidium
Asexual
Bipolar
Asexual or
bipolar
Asexual or
bipolar
Although Malassezia globosa is hypothesized to be bipolar based
on the putative MAT locus, mating has never been observed (Xu et al.,
2007).
usually monokaryotic and alternates with a dikaryotic hyphal
phase. Monomorphic species include the mushrooms and
the rusts, where spores germinate by production of hyphae,
and a number of exclusively asexual yeasts (Bandoni, 1995;
Boekhout et al., 1998).
Most sexual basidiomycete yeasts have a dimorphic life
cycle (Fig. 1). Initially, a haploid basidiospore (either a
forcibly discharged ballistospore or a budded sporidium/
statismospore) germinates to produce the free-living yeast.
The yeast state can colonize a variety of substrata, and may
be saprobic on soil or aquatic habitats, or epiphytic on
plants. Basidiomycete yeasts can reproduce asexually by
enteroblastic budding or via production of ballistoconidia
(Fell et al., 2001). In the presence of a partner of compatible
mating type, yeast cells produce conjugation tubes and
ultimately fuse to produce a dikaryotic hyphal cell. Basidiomycetes characteristically maintain a prolonged dikaryotic
state, where each cell possesses two unfused parental nuclei,
and undergo a complex mode of mitosis involving the
formation of clamp cells. Nuclear fusion and meiosis occur
in a basidium to produce a tetrad of haploid basidiospores
(Casselton & Olesnicky, 1998). In fungi, the asexual (mitosporic) and sexual (meiosporic) forms are known as the
Fig. 1. Two paradigms of dimorphic basidiomycete pathogenesis. The single-celled yeast form of the smut Ustilago maydis (left) is nonpathogenic.
Upon mating with a compatible partner, the fungus switches morphology to an infectious hyphal form, where it can invade a host plant. The singlecelled yeast form of Cryptococcus neoformans (right) switches to a dikaryotic hyphal form after mating, which may potentially be free-living,
phytopathogenic or mycoparasitic. Karyogamy and meiosis later occur in the basidium, where chains of the potentially infectious basidiospores are
produced. Crucial to both fungi is the act of sexual reproduction and a dimorphic switch between a yeast and a hyphal form to initiate infection of a
plant or an animal host.
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FEMS Yeast Res 9 (2009) 161–177
163
Sexual reproduction in pathogenic yeasts
‘anamorph’ and the ‘teleomorph’, respectively (Seifert &
Gams, 2001).
Apart from the intensively studied smut fungi, little is
known about the hyphal phase of most species in the
environment. However, the majority of dimorphic basidiomycetes are parasitic in the hyphal phase, usually on plant
or fungal hosts (Bandoni, 1995). The vast majority of
the Ustilaginomycotina, including the Ustilaginomycetes and
the Exobasidiomycetes, are dimorphic and phytopathogenic,
and in the case of the smut fungi, the hyphal phase is an
obligate parasite. Plant pathogens are also common in the
smuts of the Microbotryomycetes of the Pucciniomycotina,
while the only dimorphic members of the Pucciniomycetes,
the Septobasidiales, are entomopathogenic (Bauer et al.,
2001). Mycoparasitism appears to be a common strategy
among dimorphic basidiomycetes, and is often associated
with the presence of haustoria, colacosomes or lenticular
body organelles (Bandoni, 1995). Mycoparasites are widespread in the Pucciniomycotina, particularly the Agaricostilbomycetes, Cystobasidiomycetes and the Microbotryomycetes,
and many species currently considered to be saprobic may
be capable of parasitizing fungi (Swann et al., 2001). Most of
the Tremellomycetes have been proposed to be mycoparasitic
in their dikaryotic hyphal form (Bandoni, 1995; Wells &
Bandoni, 2001). Intriguingly, these changes between the
yeast and the hyphal form may potentially be linked with
pathogenicity in the dimorphic basidiomycetes via the
process of sexual reproduction (Madhani & Fink, 1998;
Nadal et al., 2008).
Sexual reproduction in pathogenic fungi
The majority of eukaryotes undergo sexual reproduction
between two individuals to produce recombinant, genetically
distinct progeny (Otto & Nuismer, 2004). Sexual reproduction increases genetic variability within a population and can
create individuals with increased or decreased fitness (Barton
& Charlesworth, 1998). Despite the substantial energy cost
associated with sexual reproduction, it is generally considered
to be a broadly beneficial process (Goddard et al., 2005).
Within the Ascomycota, sexual reproduction is widespread among the plant pathogens, such as Magnaporthe
oryzae and Leptosphaeria maculans (Sexton & Howlett,
2006). In contrast, the absence of a sexual cycle appears to
be commonplace among animal pathogens. In Candida
albicans, the most common human fungal pathogen,
evidence for meiosis is yet to be found despite the recent
elucidation of the MAT locus, mating and a parasexual cycle
(Hull & Johnson, 1999; Hull et al., 2000; Magee & Magee,
2000; Bennett & Johnson, 2003). Sexual reproduction
remains similarly elusive in Aspergillus fumigatus, despite
the presence of a sexual cycle in its close relative Neosartorya
fischeri and population genetic studies that suggest the occurFEMS Yeast Res 9 (2009) 161–177
rence of meiotic recombination outside the host (Paoletti
et al., 2005). Accordingly, infections involving animal pathogenic ascomycetes are generally acquired via inhalation of
infectious cells produced through asexual modes of reproduction, such as airborne conidia and arthroconidia.
In contrast to this paradigm is the prevalence of sexual
reproduction in the pathogenesis of the dimorphic basidiomycetes. Although the plant-infecting smut fungi can persist
in an asexual saprophytic yeast phase, sexual reproduction
and host invasion are essential for completion of the life
cycle. Similarly, most dimorphic basidiomycetes parasitize
plants or fungi only in the sexual hyphal phase (Boekhout
et al., 1998). On the other hand, there are a number of
emerging human pathogens from the Basidiomycota that
infect in the yeast form. In some of these species, particularly
Cryptococcus neoformans, it has been suggested that the
infectious agent may be the sexually produced basidiospores, and a dimorphic transition from the hyphal to the
yeast form may be important to initiate the infection process
(Cohen et al., 1982; Heitman, 2006).
The molecular basis of sexual
compatibility: the MAT loci
Sexual reproduction in fungi is governed by the mating type
(MAT) locus, a specialized genomic region that confers
cell-type identity. Fungi can be self-compatible for mating,
with no need for a genetically distinct mate (homothallic),
self-incompatible for mating (heterothallic) or, counterintuitively, a combination of the two. Homothallism is
characterized by dikaryotic hyphal cells that develop in the
absence of another mating partner (Whitehouse, 1949;
Deacon, 1997). In heterothallic species, two cells of a
compatible mating type conjugate and produce a dikaryotic
mycelium (Fell et al., 2001). In many heterothallic basidiomycete fungi, two distinct genetic loci reside in the MAT
locus and determine sexual compatibility: one locus encodes
homeodomain transcription factors, while the other
encodes pheromones and pheromone receptors. These genes
establish the ‘sex’ of the organism, enable self-non-self
recognition and regulate the formation and progression of
the dikaryotic sexual form. When these two loci are unlinked in the genome, the organism is termed ‘tetrapolar’,
and four possible mating types can segregate independently
at meiosis (Fraser & Heitman, 2003; Giraud et al., 2008).
Alternatively, if the pheromone/receptor locus and the
homeodomain locus form one contiguous locus that segregates as a single unit at meiosis, the organism is termed
‘bipolar’. Bipolar species are widespread in the Basidiomycota and include the oleaginous red yeast Rhodosporidium
toruloides of the Pucciniomycotina, the sugarcane smut
fungus Ustilago scitaminea of the Ustilaginomycotina and
the encapsulated yeast Cryptococcus gattii of the
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164
Agaricomycotina (Fischer & Holton, 1957; Fell et al., 2001).
In the Ascomycota and the Glomeromycota, the MAT locus is
generally small in size and invariably encodes one or more
transcription factors; although other genes may be present
in the locus, the pheromone and pheromone receptor genes
are absent (Butler et al., 2004; Idnurm et al., 2008).
Tetrapolarity is a feature unique to the Basidiomycota. An
estimated 55–65% of the agaricomycete mushrooms are
tetrapolar, often with dozens of alleles at each locus, leading
to potentially thousands of mating types (Raper, 1966). A
number of other species from all three basidiomycete
subphyla have a tetrapolar mating system, such as the
mycoparasitic jelly fungus Tremella mesenterica of the
Agaricomycotina, the psychrophilic yeast Leucosporidium
scottii of the Pucciniomycotina and the phytopathogenic
smut Ustilago maydis from the Ustilaginomycotina (Fell
et al., 2001). Although the idea is contentious, tetrapolarity
has been proposed to be the ancestral state of the Basidiomycota, and various models have proposed the derivation of
a bipolar mating type from the tetrapolar state (Raper, 1966;
Burnett, 1975; Bakkeren et al., 1992; Hibbett & Donoghue,
2001; Fraser et al., 2004; Fraser & Heitman, 2004).
To attract a partner, fungi can produce signalling molecules to indicate both their presence in the environment and
their mating compatibility. Such pheromone production has
been studied extensively in the model ascomycete Saccharomyces cerevisiae. The first stage involves the production of
a-factor or a-factor precursor molecules, short polypeptides
that undergo extensive post-translational modifications to
yield the mature pheromone (Kurjan & Herskowitz, 1982).
Following export, the pheromone molecule binds with a
cognate heterotrimeric G-protein-coupled receptor found
on cells of the opposite mating type; the a-factor binds to the
Ste3 receptor on a cells, while the a-factor binds to the Ste2
receptor on a cells (Bender & Sprague, 1986). Binding of the
ligand initiates a mitogen-activated protein (MAP) kinase
cascade that leads to cell cycle arrest, the formation of a
projection from the cell in the direction of the pheromone
gradient and cell fusion (Leberer et al., 1997). The
S. cerevisiae genes encoding pheromones and receptors do
not lie in a specialized region of the genome, and while all
cells have the genetic material required for the production of
both pheromones, they only produce the one appropriate
for their mating type (Herskowitz et al., 1992).
In the basidiomycetes, the pheromone and receptor genes
are often encoded within a MAT locus, and are a determinant of mating type. Only homologues of the a-factor
pheromone and its corresponding Ste3 receptor type are
found, and never the alternate a-factor/Ste2 receptor system, which appears to be unique to the Ascomycota (Fraser
et al., 2007). Surprisingly, even the agaricomycete mushrooms use a pheromone/receptor system (Fig. 2), despite the
fact that mushroom hyphae fuse indiscriminately (Wend2009 Federation of European Microbiological Societies
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C.A. Morrow & J.A. Fraser
land et al., 1995; O’Shea et al., 1998). In this case, coupling
of a compatible pheromone and receptor in the mushrooms
appears to be essential for maintenance of the dikaryotic cell
and not initial mate attraction (Vaillancourt et al., 1997;
Casselton & Olesnicky, 1998).
After cell fusion, the compatibility of the two mating
partners is determined intracellularly by two MAT-encoded
regulatory transcription factors. In the Ascomycota, the MAT
locus can encode transcription factors of three different
types: homeodomain, a-box or HMG (Butler et al., 2004).
The S. cerevisiae MAT locus for example encodes one of two
distinct homeodomain proteins, HD1 (a2) in MATa and
HD2 (a1) in MATa, which dimerize in diploid cells to form a
transcriptional repressor of haploid-specific genes (Ho et al.,
1994). In the Basidiomycota, the transcription factors
encoded in MAT always contain the homeodomain DNAbinding motif, and the system encodes genes of the two
classes found in S. cerevisiae, HD1 and HD2 (Casselton &
Challen, 2006). The tetrapolar mushroom fungi Coprinopsis
cinerea and Schizophyllum commune both use multiallelic
HD1 and HD2 homeodomain proteins encoded at two
subloci to generate multiple mating specificities, as each
protein can only dimerize with alternate alleles from a
different mating type (Fig. 2) (Stankis et al., 1992; Tymon
et al., 1992; Banham et al., 1995).
Maintenance of the ensuing dikaryon is under the regulation of both the homeodomain and the pheromone/receptor
loci. The homeodomain locus represses asexual sporulation,
coordinates nuclear pairing and division, septation and
clamp cell formation during mitosis (Raper, 1966; Tymon
et al., 1992). The pheromone/receptor locus regulates nuclear migration and dissolution of the septa separating cells, as
well as clamp cell fusion during mitosis of dikaryotic cells
(Raper, 1966; Wendland et al., 1995; O’Shea et al., 1998).
Semi-obligate pathogenesis: the smut
fungi
The smuts are a widespread group of dimorphic phytopathogenic basidiomycetes belonging to either the Ustilaginomycotina for example Ustilago spp., or the Pucciniomycotina for
example Microbotryum spp. (Table 1), which almost exclusively infect angiosperms (flowering plants) (Fischer & Holton, 1957). The majority of smuts are heterothallic, with a
saprobic yeast state that can propagate asexually by budding
(Bauer et al., 2001). The yeast state can colonize a variety of
substrata, but little is known regarding their ecology or
distribution in the environment (Boekhout et al., 1998). Two
cells of compatible mating types can fuse to develop an
infectious, dikaryotic hyphal appressorium, which can proceed to invade an appropriate host plant (Vanky, 1987).
During infection, the fungus usually grows asymptomatically
inside the host plant in hyphal form. The smut proliferates,
FEMS Yeast Res 9 (2009) 161–177
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Sexual reproduction in pathogenic yeasts
Fig. 2. Tetrapolar MAT loci of the Basidiomycota. In the tetrapolar system, mating type is determined by two unlinked genomic loci – the pheromone/
receptor locus (a in smuts and B in mushrooms) and the homeodomain locus (b in smuts and A in mushrooms). Where present in the smut fungi, the
pheromone locus has few alleles (biallelic in Ustilago maydis and triallelic in Sporisorium reilianum), while the separate homeodomain locus is multiallelic
(19 alleles in U. maydis and 5 alleles in S. reilianum). The tetrapolar mating type is uncommon among the smuts. In contrast, tetrapolarity is widespread
among the mushroom fungi, where multiple alleles at both loci lead to thousands of possible mating types, as in Coprinopsis cinerea and Schizophyllum
commune. Interestingly, differing complements of pheromones and receptors and homeodomain proteins are often incorporated into the alleles of
each locus, presumably through segmental duplication and pseudogenization events. Pheromone receptor genes are represented here as red arrows,
pheromone genes as solid black arrows, homeodomain genes as white arrows and non-mating type genes as faded arrows.
possibly in response to signals from the host plant, and
eventually produces masses of sooty or ‘smutty’ teliospores
(Banuett & Herskowitz, 1996). The teliospores form in a
specialized fruiting body termed a sorus, which generally
replaces either the flowers or the seeds of the host. These
dikaryotic sexual spores can then disperse before germination, which entails karyogamy and meiosis (Fischer &
Holton, 1957; Vanky, 1987).
The smut lifestyle, involving a switch between a freeliving yeast form and an infectious, plant pathogenic hyphal
form, is enormously successful (Nadal et al., 2008). Crucially, a morphogenetic transition and sexual reproduction
are directly associated with pathogenesis. The change in
morphology is a requirement for both penetration of the
plant surface and for differentiation and proliferation within
FEMS Yeast Res 9 (2009) 161–177
the host. Notably, the fungus can only sporulate in planta;
without the host, sexual teliospores cannot be produced
(Banuett & Herskowitz, 1996; Feldbrugge et al., 2004). The
dimorphic switch exemplified by the smuts is a fundamental
determinant of pathogenicity, and a common theme among
pathogenic fungi (Bakkeren et al., 2008).
Ustilago maydis
In the corn smut U. maydis, fusion of compatible yeast cells
is governed by the pheromone signalling system of the
biallelic a locus (Fig. 2) (Kahmann & Kamper, 2004). Both
a1 and a2 encode a lipoprotein pheromone and a heterotrimeric G-protein-coupled receptor (Bolker et al., 1992;
Spellig et al., 1994). Binding of the secreted pheromone to its
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166
appropriate receptor triggers cell cycle arrest and the production of conjugation tubes in the direction of the pheromone (Durrenberger et al., 1998; Muller et al., 2003). Once
two conjugation tubes fuse, continued growth is mediated
by the b locus, which encodes the HD1 orthologue bE and
the HD2 orthologue bW (Schulz et al., 1990; Gillissen et al.,
1992). Two different alleles of bE and bW are required to
produce the active heterodimer, but unlike the simple
biallelic system of the a locus, the b locus has 35 known
alleles (Kamper et al., 1995). The bE/bW heterodimer allows
for the formation of the invasive appressorium and the
initiation of infection. The a and b loci are on separate
chromosomes and segregate independently at meiosis,
giving rise to the archetypal tetrapolar mating type.
Ustilago hordei
Ustilago hordei causes covered smut of barley and oats. The
bipolar U. hordei MAT locus is unusually large, spanning
526 kb for MAT-1 and 430 kb for MAT-2. The a and b
regions are located at opposite ends of the locus, which
is suppressed for recombination (Fig. 3) (Bakkeren &
Kronstad, 1994; Lee et al., 1999). The MAT-1 locus contains
47 predicted ORFs, although many remain uncharacterized,
and any possible relationship with pathogenicity is unclear
(Bakkeren et al., 2006). The bipolar mating type found in
U. hordei and most smuts is thought to promote an inbreeding lifestyle, as with only two mating types, a given meiotic
progeny can mate with half of its siblings (Raper, 1966).
Sporisorium reilianum
Sporisorium reilianum causes head smut of both corn and
sorghum (Martinez et al., 2002). Classical genetic studies
revealed that S. reilianum is tetrapolar, although molecular
characterization of the MAT locus revealed that while the b
locus encoding the homeodomain proteins is multiallelic
(five alleles), the pheromone/receptor a locus appears to be
triallelic, with three different pheromone/receptor loci, a1,
a2 and a3 (Fig. 2) (Schirawski et al., 2005). Interestingly,
each allele appears to encode not one but two pheromone
genes plus one receptor, in a manner similar to the mushroom fungi. These two pheromones are the ligands for the
receptors of the other two alleles, and leads to the scenario
where each mating type can successfully detect a pheromone
from the other two, but not itself, and can also produce a
pheromone detectable by both (Schirawski et al., 2005).
Microbotryum violaceum
The anther smut M. violaceum from the Pucciniomycotina
infects plants of the carnation family. The smut lifestyle
appears to have evolved twice within the Basidiomycota, as
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C.A. Morrow & J.A. Fraser
na display many similarities with regard to host infection,
morphology and teliosporogenesis, and represent a remarkable example of convergent evolution (Bauer et al., 2001).
The mating type locus of M. violaceum appears to extend
over an entire chromosome (2.8–3.1 Mb for A1 and
3.4–4.2 Mb for A2) and harbours a single pheromone
receptor plus orthologues of bE and bW (Hood, 2002;
Yockteng et al., 2007). Populations show a mating type ratio
bias, which is due to the presence of lethal alleles in the A2
mating type. As this phenotype is masked in the dikaryon,
intertetrad mating is the preferred and dominant form of
mating (Hood & Antonovics, 2000).
Opportunistic pathogenesis: the yeasts
The human pathogenic basidiomycetous yeasts are a phylogenetically diverse group, united by a shared growth form.
Single-celled yeasts have the ideal morphology to effect
pathogenesis in an animal host – for ease of entry, for
transport around the body or to penetrate certain tissues –
as demonstrated by the large number of yeast pathogens
compared with the filamentous fungal pathogens (De Hoog,
2000). Systemic infections by basidiomycete yeasts are generally acquired in one of two ways: via inhalation of an
infectious cell from the environment, or alternatively when
the yeast is allowed passage into the body, such as through
an indwelling catheter. In both cases, efficient transport
throughout the body is achieved via the bloodstream.
While there are some yeasts such as C. neoformans and
C. gattii in which sexual reproduction is thought to play a
role in the pathogenic process, in many other basidiomycetous yeasts the role of sex is poorly understood, with no
known teleomorph or sexual cycle. However, recent molecular analyses of fungi previously considered to be strictly
asexual, such as the ascomycete A. fumigatus and the
basidiomycete Malassezia globosa, have revealed predicted
MAT loci and suggested cryptic sexual behaviour. Where
sexual states are known, very little is known about the
hyphal state in the environment (Boekhout et al., 1998).
The best-known and by far the most clinically significant
basidiomycete pathogen of animals is C. neoformans,
although the commensal yeasts of the genus Malassezia also
cause a variety of common cutaneous and deep-seated
infections. With the growth in the immunocompromized
population worldwide, a number of additional basidiomycete yeasts have also recently emerged as increasingly important opportunistic pathogens of humans, including
species of Trichosporon, Rhodotorula, Sporobolomyces and
Cryptococcus (Hazen, 1995; Khawcharoenporn et al., 2007).
Cryptococcus neoformans
Cryptococcus neoformans is a ubiquitous human yeast
pathogen of the Tremellomycetes that primarily infects
FEMS Yeast Res 9 (2009) 161–177
167
Sexual reproduction in pathogenic yeasts
α
α
α
α
α
α
α
α
α
α
α
α
α
α
α
α
α
α
α
α
α
α
α
α
Fig. 3. Bipolar MAT loci of the Basidiomycota. In contrast to the small sex-determining regions of the Ascomycota, all the confirmed or putative bipolar
MAT loci of the Basidiomycota are complex genomic structures of c. 100 kb or greater. The Cryptococcus neoformans alleles are highly rearranged
between mating type, and contain a cohort of mating- and virulence- associated genes, but only one homeodomain gene per locus. The Ustilago hordei
MAT-1 locus harbours a number of repeated elements, functional genes and pseudogenes, with the pheromone/receptor and homeodomain loci at
either end. The putative MAT locus of Malassezia globosa contains predicted homeodomain genes, an STE3-type pheromone receptor gene and a
pheromone gene. Analysis of the Sporobolomyces sp. genome (v1.0) revealed the presence of divergently transcribed bE and bW orthologues on a
separate scaffold from a predicted pheromone/receptor locus; the two scaffolds may represent the same chromosome if the organism is bipolar.
Pheromone receptor genes are represented here as red arrows, pheromone genes as solid black arrows, homeodomain genes as white arrows and nonmating type genes as faded arrows. Uncharacterized genes from M. globosa and Sporobolomyces sp. are named using the closest Saccharomyces
cerevisiae or Schizosaccharomyces pombe homologues.
immunocompromized individuals, particularly AIDS
patients. Infection is primarily acquired via inhalation of
infectious cells, which disseminate to the central nervous
system to cause life-threatening meningoencephalitis
(Casadevall & Perfect, 1998). The sexual teleomorph, Filobasidiella neoformans, and a complete sexual cycle have been
described (Kwon-Chung, 1975). In C. neoformans, sexual
reproduction may potentially be associated with the infection process, because sexual development produces spores.
Although the idea remains highly controversial, the small
and easily aerosolized sexual basidiospores are thought to be
FEMS Yeast Res 9 (2009) 161–177
the most likely infectious propagule (Powell et al., 1972;
Ruiz & Bulmer, 1981; Cohen et al., 1982; Zimmer et al.,
1984; Sukroongreung et al., 1998).
The primary environmental niche of C. neoformans is
pigeon guano. In the presence of pheromones and appropriate environmental cues, compatible haploid mating
partners fuse and undergo a developmental transition to a
dikaryotic filamentous growth form. Virtually nothing is
known about the filamentous phase in the environment,
which has been proposed to be free living, plant parasitic or
mycoparasitic (Bandoni, 1995). However, successful mating
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168
and sporulation has been observed on both pigeon guano
media and live plant surfaces (Nielsen et al., 2007; Xue et al.,
2007). The dikaryon undergoes karyogamy and meiosis in a
terminal basidium, before budding off four chains of
haploid spores (Kwon-Chung, 1975).
Cryptococcus neoformans is heterothallic and bipolar (a
and a), with a large mating type locus spanning 4 100 kb
(Fig. 3). The MAT locus contains c. 25 genes in total and
includes the pheromone/receptor and homeodomain genes
(Lengeler et al., 2002; Fraser et al., 2004). Significantly, the
locus contains additional genes relating to mating and the
sexual cycle, including elements of the pheromone-responsive MAP kinase cascade, meiosis and sporulation genes. In
contrast to the basidiomycete paradigm where each mating
type encodes two homeodomain genes (one each of the
HD1 and HD2 class), C. neoformans has adopted a format
similar to the ascomycetes: MATa cells encode only Sxi1a
(HD1) while MATa cells encode only Sxi2a (HD2) (Hull
et al., 2005).
A peculiar feature of C. neoformans is the presence of a
highly skewed population ratio: nearly all isolates are of the a
mating type (Kwon-Chung & Bennett, 1978; Lengeler et al.,
2000). Furthermore, up to 50% of the population is recalcitrant to mating, and thought to be sterile. However, a number
of highly fertile a strains and a predicted recombinant
population structure (much closer to 1 : 1) have been identified from isolates from sub-Saharan Africa, suggesting that
mating may play an important role in certain regions
(Litvintseva et al., 2003, 2005). Cryptococccus neoformans
a isolates have been found to be more virulent in certain
genetic backgrounds, and a isolates have predominated in the
CNS in mixed-infection experiments with a and a isolates
(Kwon-Chung et al., 1992; Nielsen et al., 2003, 2005).
Interestingly, C. neoformans can utilize an alternate
pathway to traditional sexual development. Mating can
occur between two cells of the same mating type, resulting
in hyphal growth with unfused clamp connections, meiosis
and the production of recombinant spores in a process
known as monokaryotic fruiting (Wickes et al., 1996; Lin
et al., 2005). This would be advantageous for a species
with such a skewed population, and enables basidiospore
production and dispersal even when mating partners are
scarce (Lin et al., 2005; Nielsen et al., 2007).
Cryptococcus gattii
Cryptococcus gattii is a sibling species of C. neoformans in the
Tremellomycetes, generally restricted to tropical and subtropical climates, that predominantly infects immunocompetent hosts (Kwon-Chung, 1976; Fraser et al., 2003). As in
C. neoformans, the proposed mode of infection is via
inhalation of spores, and a complete sexual cycle and sexual
teleomorph Filobasidiella bacillispora have also been identi2009 Federation of European Microbiological Societies
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c
C.A. Morrow & J.A. Fraser
fied (Kwon-Chung, 1976; Campbell et al., 2005a). The a and
a MAT loci show a structure similar to the C. neoformans
locus: both are c. 100 kb in size and contain the same cohort
of genes, albeit highly rearranged (Fraser et al., 2004).
A recent outbreak of this fungus has occurred on Vancouver Island, Canada (Hoang et al., 2004). Interestingly, it
appears that an unusual, more virulent population of
C. gattii has managed to expand beyond its normal environmental niche into temperate climates. Despite the fact that
most isolates worldwide are sterile, almost all samples from
Vancouver are highly fertile, and are almost entirely of the a
mating type. The population is also nearly clonal, although
recent studies suggest that this more virulent strain may
have arisen recently due to a recombination event, possibly
between two parents of the same mating type (Fraser et al.,
2003, 2005). Alternatively, the outbreak strain may have
originated in South America, where this rare genotype is
more common and may be recombining in mixed a–a
populations (Kidd et al., 2004; Trilles et al., 2008).
Unusual population structures and variable mating competency have also been observed in other populations of
C. gattii. Population genetic studies from Australia have
revealed broadly clonal populations, but also identified
isolated recombining, highly fertile populations (Campbell
et al., 2005b; Saul et al., 2008). A skewed population
structure was also evident: sampled areas included populations with c. 1 : 1 mating type ratios, a hallmark of recombining populations, but an a mating type bias in others
(Halliday et al., 1999). Remarkably, surveys of C. gattii from
Colombia have revealed populations predominantly of a
isolates (c. 97%) of both clinical and environmental samples
(Escandon et al., 2006). Although the fertility and genetic
variability of these specimens were not ascertained, a population almost entirely of the a mating type would be highly
unusual, particularly in comparison with the fertile and
highly virulent clade of a mating type in Vancouver.
Intriguingly, diploid or aneuploid hybrids between C. gattii
and C. neoformans have recently been described from
clinical specimens that may potentially display unique
virulence characteristics (Bovers et al., 2006, 2008).
Cryptococcus laurentii and Cryptococcus
albidus
A variety of Cryptococcus species in the Tremellomycetes have
been implicated in a range of both localized and systemic
infections in humans, primarily C. laurentii and C. albidus.
Both C. laurentii and C. albidus are generally saprobic
and can be widely isolated from environmental sources, as
well as among the skin flora (Krajden et al., 1991). Recent
phylogenetic analyses of these species have revealed
them to be polyphyletic, which unfortunately obscures
causality between phenotype and pathogenesis (Fell
FEMS Yeast Res 9 (2009) 161–177
169
Sexual reproduction in pathogenic yeasts
et al., 2000; Fonseca et al., 2000; Sugita et al., 2000;
Takashima et al., 2003).
Infections with these species generally involve immunocompromized individuals, although invasive devices are
a predisposing factor for C. laurentii infection. Both
C. laurentii and C. albidus have been reported in cases of
cutaneous infections, as well as fungaemia, meningitis and
pulmonary infections (Kordossis et al., 1998; Averbuch
et al., 2002; Burnik et al., 2007). These species complexes
share two classical virulence factors with their more pathogenic distant relatives; both possess a polysaccharide capsule
and synthesize the antioxidant melanin (Ikeda et al., 2000,
2002). However, the ability to grow at 37 1C is rare in both
species, perhaps explaining why C. laurentii and C. albidus
are less successful pathogens than C. neoformans and
C. gattii, which can routinely grow at 37 1C (Casadevall
& Perfect, 1998).
Cryptococcus laurentii and C. albidus are considered to be
anamorphic. While a complete sexual cycle has not been
elucidated, compatible cell fusion, formation of mycelia and
possible teliospores have been reported for C. laurentii
(Kurtzman, 1973). Both complexes harbour teleomorphs in
species closely related to these pathogens, which may imply
the presence of cryptic sexuality (Fonseca et al., 2000;
Takashima et al., 2003). As cells of both species are commonly found in the air, the suggested route of infection is via
the respiratory system in a manner similar to C. neoformans
(Krajden et al., 1991; Burnik et al., 2007).
balls’ form, where both yeast and hyphal phases of the
fungus are found. Malassezia species possess virulence
factors similar to those of C. neoformans, including melanin
production and a capsule-like lipid layer that is thought to
have an immunomodulatory effect on the host immune
system during asymptomatic carriage (Ashbee, 2006;
Thomas et al., 2008). The entire genus is anamorphic, with
no identified sexual cycle. However, the taxonomic position
of the genus Malassezia within Ustilaginomycotina – a group
of anamorphic animal pathogens among a clade of nearly
exclusively sexual plant pathogens – is peculiar; it is possible
that Malassezia species are phytopathogenic in an as-yet
undetermined sexual dikaryophase (Begerow et al., 2006).
The recent completion of the genome of the dandruffcausing M. globosa has revealed the presence of a putative
MAT locus (Fig. 3) (Xu et al., 2007). The locus contains
genes encoding both pheromones and pheromone receptors
(Ste3 type) plus homeodomain-containing bE and bW
homologues. The c. 173-kb locus also contains homologues
of two genes found in the C. neoformans locus (STE12 and
CID1) and appears to be quite gene-rich (82 predicted
ORFs), but repeated element-poor in comparison with
other large MAT loci. Identification of another MAT allele
from M. globosa could potentially enable the elucidation of
the process of mating and sexual reproduction in the
species, as the mating type genes do not appear to be
degraded as may be expected from a strictly asexual species.
Trichosporon
Malassezia
The genus Malassezia consists of a small group of common
human commensal yeasts classified with the primarily
phytopathogenic Ustilaginomycotina. Besides C. neoformans,
Malassezia spp. are the most clinically prevalent basidiomycete human pathogens, responsible for a range of cutaneous
infections including pityriasis versicolor and seborrhoeic
dermatitis, and also causing a number of systemic mycoses
in immunosuppressed patients, including catheter-related
fungaemia, peritonitis and meningitis (Ashbee & Evans,
2002). Recent taxonomic revision of the genus has led to
the recognition of a number of new species, with the most
commonly isolated pathogenic species including Malassezia
furfur, M. globosa, Malassezia sympodialis, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae and
Malassezia obtusa (Gueho et al., 1996). All species in the
genus, except for M. pachydermatis, are fatty acid auxotrophs and are therefore obligate commensals. As a consequence, these yeasts require an external lipid source in
culture, which often has a confounded diagnosis (Shifrine
& Marr, 1963; Xu et al., 2007).
Malassezia species are dimorphic with cutaneous infections, often presenting a characteristic ‘spaghetti and meatFEMS Yeast Res 9 (2009) 161–177
The genus Trichosporon contains a number of yeast species
responsible for both superficial and systemic mycoses in
humans, characterized by the presence of true hyphae and
arthroconidia (Middelhoven et al., 2004). Following recent
taxonomic reclassification of Trichosporon beigelii, six species of Trichosporon are implicated in human infection:
Trichosporon asahii, Trichosporon mucoides, Trichosporon
cutaneum, Trichosporon asteroides, Trichosporon inkin and
Trichosporon ovoides (Gueho et al., 1992). Infections range
from superficial mycoses (particularly white piedra) to
invasive and systemic mycoses, including fungaemia, pneumonia and meningitis. The major cause of disseminated
trichosporonosis is T. asahii, which has emerged as an
increasingly important pathogen primarily of immunocompromized patients; note that since reclassification, most
previous cases of T. beigelii-invasive trichosporonosis have
been ascribed to T. asahii (Anaissie & Bodey, 1991; Walsh
et al., 2004).
Trichosporon asahii can be found as both an environmental saprophyte and as part of the skin flora, and infection is
associated with haematological malignancies, AIDS or corticosteroid usage. Although infection is commonly associated with the presence of invasive devices such as catheters,
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170
T. asahii is also thought to enter via the respiratory and
gastrointestinal tracts (Walsh et al., 1992, 2004; Tashiro
et al., 1995). Trichosporon asahii accounts for nearly 10% of
disseminated fungal infections, and is associated with a
generally poor prognosis and high mortality rate (approaching 80%) with a variable response to antifungal treatment
(Krcmery et al., 1999; Di Bonaventura et al., 2006).
Infection with T. asahii presents with physical and histopathological symptoms similar to disseminated candidiasis,
which can often result in misdiagnosis. Significantly, the
fungus is able to change morphology among the yeast,
hyphal and pseudohyphal forms during infection in a manner similar to C. albicans, although the presence of arthroconidia in T. asahii infections is characteristic (Tashiro et al.,
1994). Trichosporon asahii also expresses an antigen similar
to cryptococcal glucuronoxylomannan, which has an immunosuppressive effect on the host (Lyman et al., 1995). No
sexual teleomorph has been identified in the genus, however; only asexual reproduction has been found to date
(Middelhoven et al., 2004).
Rhodotorula
The Rhodotorula species are a polyphyletic group of yeasts
distributed in both Pucciniomycotina and Ustilaginomycotina, which can be isolated widely from the environment and
normal human biota. Three pucciniomycete species have
been identified as causing infections in humans: Rhodotorula
mucilaginosa (formerly Rhodotorula rubra), Rhodotorula
glutinis and Rhodotorula minuta. Rhodotorula mucilaginosa
is most commonly isolated from patients (c. 70%) (Tuon &
Costa, 2008). Similar to other emerging pathogenic yeasts,
all three species are primarily pathogens of the immunocompromized, and are frequently associated with indwelling
catheters. Infections commonly associated with R. mucilaginosa include endocarditis, peritonitis and meningitis, but
fungaemia is most common (Thakur et al., 2007; Tuon et al.,
2007). Rhodotorula mucilaginosa and R. glutinis can be
recalcitrant to treatment, and are known for being highly
resistant to fluconazole; mortality rates for R. mucilaginosa
infection have been reported to be as high as 15% (Diekema
et al., 2005; Neofytos et al., 2007).
Rhodotorula mucilaginosa and R. glutinis are both anamorphic yeasts of the Microbotryomycetes, while R. minuta is
an anamorphic yeast of the Cystobasidiomycetes. Recent
taxonomic re-evaluation of R. glutinis, however, revealed
significant genetic heterogeneity, and a number of isolates
previously ascribed to R. glutinis have been reclassified as
five separate sexual teleomorphs in the genus Rhodosporidium, rendering any correlations between lifestyle and
infection in previous clinical cases extremely difficult
(Gadanho et al., 2001; Sampaio et al., 2001; Gadanho
& Sampaio, 2002). All three anamorphic Rhodotorula
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C.A. Morrow & J.A. Fraser
species are closely related to a number of teleomorphic
species, however, and future study may yet reveal the
presence of cryptic sexuality (Biswas et al., 2001; Gadanho
& Sampaio, 2002).
Recently, a portion of the MAT locus of the closely related
bipolar microbotryomycete yeast R. toruloides was sequenced, revealing the presence of multiple pheromone
precursor genes, a p21-activated kinase (PAK) gene similar
to the pheromone-responsive MAP kinase component
STE20 located in the MAT locus of C. neoformans and an
STE3-type pheromone receptor gene (Coelho et al., 2008).
No putative homeodomain genes have been located thus far
in close proximity to the pheromone locus.
Sporobolomyces
The genus Sporobolomyces is a polyphyletic assemblage of
yeasts within the Pucciniomycotina that produce forcibly
discharged asexual ballistoconidia. Sporobolomyces is found
as both a widespread environmental saprophyte and as a
common human commensal, and three species have been
reported to be pathogenic in humans: Sporobolomyces
roseus, Sporobolomyces holsaticus and Sporobolomyces salmonicolor. The latter species has primarily been implicated in
human infection, including reports of dermatitis, fungaemia, lymphadenitis and endophthalmitis, in association
with both immunocompetent and AIDS patients (Plazas
et al., 1994; Sharma et al., 2006). Sporobolomyces salmonicolor has shown resistance to both fluconazole and amphotericin B in vitro, although standard antifungal therapies have
often resolved infections (Serena et al., 2004).
Sporobolomyces salmonicolor has an identified teleomorph, Sporidiobolus salmonicolor (Van der Walt, 1970).
The very closely related species Sporidiobolus johnsonii,
considered a synonym of S. holsaticus, is primarily homothallic and may be in the process of speciation from
Sporobolomyces salmonicolor due to limited sexual compatibility between the two (Valerio et al., 2008b). Sporobolomyces roseus, which has long been considered asexual, has a
recently described sexual teleomorph, Sporidiobolus metaroseus, although only self-fertile isolates have been found so
far (Valerio et al., 2008a). It is unclear whether the asexual or
the sexual state is the infectious form.
The genome of S. roseus was recently made available
(http://www.genome.jgi.doe.gov); however, the strain sequenced has since been revealed as an undescribed Sporobolomyces species of unknown sexuality and mating type
(Valerio et al., 2008a). Nevertheless, the genome sequence
for this closely related species reveals potential unlinked
homeodomain and pheromone/receptor loci (Fig. 3). The
pheromone/receptor locus contains three copies of a
pheromone precursor, plus an STE20 homologue and an
STE3-type receptor, and appears syntenic to the partial
FEMS Yeast Res 9 (2009) 161–177
171
Sexual reproduction in pathogenic yeasts
pheromone locus elucidated in R. toruloides (Coelho et al.,
2008). The homeodomain locus contains both HD1 and
HD2 homologues, which appear intact and are divergently
transcribed (unpublished data). The two regions could
potentially form a large, contiguous locus (Z1700 kb)
spanning the majority of the chromosome, in a similar
manner to the large MAT loci of both U. hordei and
M. violaceum.
Conclusion and outlook: sex, morphology
and infection
Comparison between mechanisms of pathogenesis of basidiomycete yeasts on both human and plant hosts reveals
vastly different approaches to a pathogenic lifestyle. Central
to both modes of infection, however, is a change in the
morphology of the fungus between yeast and hyphal growth
forms, and potentially, the requirement for sexual reproduction. Links between sexual development and pathogenesis
have been suggested previously for a number of dimorphic
fungi, particularly in signalling pathways (Madhani & Fink,
1998; Nadal et al., 2008).
Animal pathogenic yeasts tend to infect in the yeast form,
which enables ease of entry into the host and movement via
the bloodstream. The respiratory system may be a common
portal for many opportunistic basidiomycete yeast pathogens of humans, particularly Cryptococcus species. However,
the filamentous sexual form may potentially be required to
produce the infectious particle. In the plant pathogens,
while the asexual yeast form can survive epiphytically on
the host, it must locate an appropriate partner to initiate
infection. Pathogenesis is intimately linked to a dimorphic
transition, as the fungus changes from a yeast to a hyphal
growth form and invades the host plant. The reverse is
extremely uncommon within the basidiomycetes – infection
of humans with filamentous basidiomycete fungi is limited
to sporadic accounts of infection with S. commune and
C. cinerea (Rihs et al., 1996; Lagrou et al., 2005); similarly,
yeast infections of plants are rare (Fell et al., 2001).
There are few pathogenic fungi that can infect both plant
and animal hosts, due to the different mechanisms and
morphology required to effect pathogenesis. Within the
basidiomycetes, U. maydis has been sporadically implicated
in human infections; however, the yeast state appears to be
the infectious form (Preininger, 1937; Moore et al., 1946;
Patel et al., 1995). Yeast anamorphs of the normally filamentous, plant pathogenic Ustilaginomycetes have been
shown to infect humans, including Pseudozyma and Malassezia species (Sugita et al., 2003). Conversely, under laboratory conditions, both C. neoformans and C. gattii have
recently been shown to infect Arabidopsis thaliana, causing
dwarfing and chlorosis in the host plant. Correspondingly, it
was the dikaryotic filamentous form produced via mating of
FEMS Yeast Res 9 (2009) 161–177
a and a yeast isolates on seedlings that was pathogenic (Xue
et al., 2007). However, many basidiomycete yeast species
such as C. neoformans and C. gattii may potentially be
mycoparasitic in their hyphal form (Bandoni, 1995).
Further ties between the process of sexual reproduction
and pathogenesis are found in the mating type locus itself:
in C. neoformans and C. gattii, a number of gene products
located in MAT have been implicated in virulence, including
the transcription factor gene STE12, the pheromone receptor gene STE3 and the PAK kinase gene STE20 (Chang et al.,
2000; Wang et al., 2002). Interestingly, STE12 is also located
in the putative MAT locus of M. globosa and c. 80 kb
downstream of STE3 in Sporobolomyces sp.; STE20 in
Sporobolomyces sp. also lies directly between two pheromone
genes. MAT locus genes of C. neoformans including the
pheromone genes are also induced during infection, and the
two mating types display different virulence properties
(Nielsen et al., 2003, 2005; Heitman, 2006). A number
of ongoing basidiomycete genome projects (including the
T. mesenterica, C. laurentii, U. hordei and S. reilianum
genomes) may reveal further insights into MAT evolution
and virulence.
Although a number of the basidiomycetous yeast pathogens are currently considered to be exclusively asexual, many
of these ‘asexual’ fungi retain the machinery to undergo sex,
but perhaps utilize it only rarely (Nielsen & Heitman, 2007).
Remarkably, molecular analysis and genome sequencing are
consistently confirming that these asexual species are either
engaging in sexual recombination, or possess intact MAT
loci. Examples from the Ascomycota include C. albicans,
Coccidioides immitis and Coccidioides posadasii, Penicillium
marneffei and A. fumigatus (Burt et al., 1996; Koufopanou
et al., 1997; Hull & Johnson, 1999; Paoletti et al., 2005; Woo
et al., 2006). Similarly, in the Basidiomycota, the potential
MAT locus in the genome of M. globosa suggests the presence of cryptic sex in Malassezia, and a sexual teleomorph
has recently been described for S. roseus (Xu et al., 2007;
Valerio et al., 2008a).
Drawing correlations between the pathogenesis and the
lifestyle of many of the basidiomycete yeasts is challenging;
all the genera reported to infect humans have recently
undergone extensive phylogenetic reclassification, and many
of the original clinical reports now refer to obsolete species,
or species that have undergone revision. While dimorphism
and sexual reproduction is clearly linked to the pathogenesis
of the smut fungi, the exact nature of the infectious particle
in the yeasts is less clear; while the sexually produced
basidiospore has been implicated in Cryptococcus species,
this remains a subject of debate. Additionally, information
on the hyphal phases of most yeasts is fragmentary for even
the best-studied systems. The emerging molecular data,
combined with a greater understanding of the ecology of
dimorphic basidiomycetes, should provide a greater insight
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172
into the potential role of sexual reproduction in these
important emerging pathogens.
References
Aime MC, Matheny PB, Henk DA et al. (2006) An overview of the
higher level classification of Pucciniomycotina based on
combined analyses of nuclear large and small subunit rDNA
sequences. Mycologia 98: 896–905.
Anaissie E & Bodey GP (1991) Disseminated trichosporonosis:
meeting the challenge. Eur J Clin Microbiol 10: 711–713.
Ashbee HR (2006) Recent developments in the immunology and
biology of Malassezia species. FEMS Immunol Med Mic 47:
14–23.
Ashbee HR & Evans EG (2002) Immunology of diseases
associated with Malassezia species. Clin Microbiol Rev 15:
21–57.
Averbuch D, Boekhout T, Falk R, Engelhard D, Shapiro M, Block
C & Polacheck I (2002) Fungemia in a cancer patient caused by
fluconazole-resistant Cryptococcus laurentii. Med Mycol 40:
479–484.
Bakkeren G & Kronstad JW (1994) Linkage of mating type loci
distinguishes bipolar from tetrapolar mating in
basidiomycetous smut fungi. P Natl Acad Sci USA 91:
7085–7089.
Bakkeren G, Gibbard B, Yee A, Froeliger E, Leong S & Kronstad J
(1992) The a loci and b loci of Ustilago maydis hybridize with
DNA sequences from other smut fungi. Mol Plant Microbe In
5: 347–355.
Bakkeren G, Jiang G, Warren RL et al. (2006) Mating factor
linkage and genome evolution in basidiomycetous pathogens
of cereals. Fungal Genet Biol 43: 655–666.
Bakkeren G, Kamper J & Schirawski J (2008) Sex in smut fungi:
structure, function and evolution of mating type complexes.
Fungal Genet Biol 45 (suppl 1): S15–S21.
Bandoni RJ (1995) Dimorphic heterobasidiomycetes: taxonomy
and parasitism. Stud Mycol 38: 13–27.
Banham AH, Asante-Owusu RN, Gottgens B, Thompson S,
Kingsnorth CS, Mellor E & Casselton LA (1995) An
N-terminal dimerization domain permits homeodomain
proteins to choose compatible partners and initiate sexual
development in the mushroom Coprinus cinereus. Plant Cell 7:
773–783.
Banuett F & Herskowitz I (1996) Discrete developmental stages
during teliospore formation in the corn smut fungus, Ustilago
maydis. Development 122: 2965–2976.
Barton NH & Charlesworth B (1998) Why sex and
recombination? Science 281: 1986–1990.
Bauer R, Begerow D, Oberwinkler F, Piepenbring M & Berbee M
(2001) Ustilaginomycetes. The Mycota VII, Part B. Systematics
and Evolution (McLaughlin DJ, McLaughlin EG & Lemke PA,
eds), pp. 57–83. Springer-Verlag, Berlin.
Begerow D, Stoll M & Bauer R (2006) A phylogenetic hypothesis
of Ustilaginomycotina based on multiple gene analyses and
morphological data. Mycologia 98: 906–916.
2009 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
c
C.A. Morrow & J.A. Fraser
Bender A & Sprague Jr GF (1986) Yeast peptide pheromones,
a-factor and alpha-factor, activate a common response
mechanism in their target cells. Cell 47: 929–937.
Bennett RJ & Johnson AD (2003) Completion of a parasexual
cycle in Candida albicans by induced chromosome loss in
tetraploid strains. EMBO J 22: 2505–2515.
Biswas SK, Yokoyama K, Nishimura K & Miyaji M (2001)
Molecular phylogenetics of the genus Rhodotorula and related
basidiomycetous yeasts inferred from the mitochondrial
cytochrome b gene. Int J Syst Evol Micr 51: 1191–1199.
Boekhout T, Bandoni RJ, Fell JW & Kwon-Chung KJ (1998)
Discussion of teleomorphic and anamorphic genera of
heterobasidiomycetous yeasts. The Yeasts: A Taxonomic Study,
4th edn (Kurtzman CP & Fell JW, eds), pp. 609–625. Elsevier,
Amsterdam.
Bolker M, Urban M & Kahmann R (1992) The a mating type
locus of U. maydis specifies cell signaling components. Cell 68:
441–450.
Bovers M, Hagen F, Kuramae EE, Diaz MR, Spanjaard L, Dromer
F, Hoogveld HL & Boekhout T (2006) Unique hybrids between
the fungal pathogens Cryptococcus neoformans and
Cryptococcus gattii. FEMS Yeast Res 6: 599–607.
Bovers M, Hagen F, Kuramae EE, Hoogveld HL, Dromer F, StGermain G & Boekhout T (2008) AIDS patient death caused
by novel Cryptococcus neoformans C. gattii hybrid. Emerg
Infect Dis 14: 1105–1108.
Burnett JH (1975) Mycogenetics. John Wiley & Sons, London.
Burnik C, Altintas ND, Ozkaya G, Serter T, Selcuk ZT, Firat P,
Arikan S, Cuenca-Estrella M & Topeli A (2007) Acute
respiratory distress syndrome due to Cryptococcus albidus
pneumonia: case report and review of the literature. Med
Mycol 45: 469–473.
Burt A, Carter DA, Koenig GL, White TJ & Taylor JW (1996)
Molecular markers reveal cryptic sex in the human pathogen
Coccidioides immitis. P Natl Acad Sci USA 93: 770–773.
Butler G, Kenny C, Fagan A, Kurischko C, Gaillardin C & Wolfe
KH (2004) Evolution of the MAT locus and its Ho
endonuclease in yeast species. P Natl Acad Sci USA 101:
1632–1637.
Campbell LT, Currie BJ, Krockenberger M, Malik R, Meyer W,
Heitman J & Carter DA (2005a) Clonality and recombination
in genetically differentiated subgroups of Cryptococcus gattii.
Eukaryot Cell 4: 1403–1409.
Campbell LT, Fraser JA, Nichols CB, Dietrich FS, Carter DA &
Heitman J (2005b) Clinical and environmental isolates of
Cryptococcus gattii from Australia that retain sexual fecundity.
Eukaryot Cell 4: 1410–1419.
Casadevall A & Perfect JR (1998) Cryptococcus neoformans. ASM
Press, Washington, DC.
Casselton LA & Challen MP (2006) The mating type genes of the
basidiomycetes. The Mycota I: Growth, Differentiation and
Sexuality, 2nd edn (Kues U & Fischer R, eds), pp. 357–374.
Springer-Verlag, Berlin.
FEMS Yeast Res 9 (2009) 161–177
173
Sexual reproduction in pathogenic yeasts
Casselton LA & Olesnicky NS (1998) Molecular genetics of
mating recognition in basidiomycete fungi. Microbiol Mol Biol
R 62: 55–70.
Chang YC, Wickes BL, Miller GF, Penoyer LA & Kwon-Chung KJ
(2000) Cryptococcus neoformans STE12alpha regulates
virulence but is not essential for mating. J Exp Med 191:
871–882.
Coelho MA, Rosa A, Rodrigues N, Fonseca A & Goncalves P
(2008) Identification of mating type genes in the bipolar
basidiomycetous yeast Rhodosporidium toruloides: first insight
into the MAT locus structure of the Sporidiobolales. Eukaryot
Cell 7: 1053–1061.
Cohen J, Perfect JR & Durack DT (1982) Cryptococcosis and the
basidiospore. Lancet 8284: 1301.
Deacon JW (1997) Modern Mycology. Blackwell Science, Oxford.
De Hoog GS (2000) Atlas of Clinical Fungi. Centraalbureau voor
Schimmelcultures, Utrecht, the Netherlands.
Di Bonaventura G, Pompilio A, Picciani C, Iezzi M, D’Antonio D
& Piccolomini R (2006) Biofilm formation by the emerging
fungal pathogen Trichosporon asahii: development,
architecture, and antifungal resistance. Antimicrob Agents Ch
50: 3269–3276.
Diekema DJ, Petroelje B, Messer SA, Hollis RJ & Pfaller MA
(2005) Activities of available and investigational antifungal
agents against Rhodotorula species. J Clin Microbiol 43:
476–478.
Durrenberger F, Wong K & Kronstad JW (1998) Identification of
a cAMP-dependent protein kinase catalytic subunit required
for virulence and morphogenesis in Ustilago maydis. P Natl
Acad Sci USA 95: 5684–5689.
Escandon P, Sanchez A, Martinez M, Meyer W & Castaneda E
(2006) Molecular epidemiology of clinical and environmental
isolates of the Cryptococcus neoformans species complex reveals
a high genetic diversity and the presence of the molecular type
VGII mating type a in Colombia. FEMS Yeast Res 6: 625–635.
Feldbrugge M, Kamper J, Steinberg G & Kahmann R (2004)
Regulation of mating and pathogenic development in Ustilago
maydis. Curr Opin Microbiol 7: 666–672.
Fell JW, Boekhout T, Fonseca A, Scorzetti G & Statzell-Tallman A
(2000) Biodiversity and systematics of basidiomycetous yeasts
as determined by large-subunit rDNA D1/D2 domain
sequence analysis. Int J Syst Evol Micr 50: 1351–1371.
Fell JW, Boekhout T, Fonseca A & Sampaio JP (2001)
Basidiomycetous yeasts. The Mycota VII, Part B. Systematics
and Evolution (McLaughlin DJ, McLaughlin EG & Lemke PA,
eds), pp. 1–36. Springer-Verlag, Berlin.
Fischer GW & Holton CS (1957) Biology and Control of the Smut
Fungi. Ronald Press Company, New York.
Flegel TW (1977) Let’s call a yeast a yeast. Can J Microbiol 23:
945–946.
Fonseca A, Scorzetti G & Fell JW (2000) Diversity in the yeast
Cryptococcus albidus and related species as revealed by
ribosomal DNA sequence analysis. Can J Microbiol 46: 7–27.
Fraser JA & Heitman J (2003) Fungal mating type loci. Curr Biol
13: R792–R795.
FEMS Yeast Res 9 (2009) 161–177
Fraser JA & Heitman J (2004) Evolution of fungal sex
chromosomes. Mol Microbiol 51: 299–306.
Fraser JA, Subaran RL, Nichols CB & Heitman J (2003)
Recapitulation of the sexual cycle of the primary fungal
pathogen Cryptococcus neoformans var. gattii: implications for
an outbreak on Vancouver Island, Canada. Eukaryot Cell 2:
1036–1045.
Fraser JA, Diezmann S, Subaran RL, Allen A, Lengeler KB,
Dietrich FS & Heitman J (2004) Convergent evolution of
chromosomal sex-determining regions in the animal and
fungal kingdoms. PLoS Biol 2: 2243–2255.
Fraser JA, Giles SS, Wenink EC et al. (2005) Same-sex mating and
the origin of the Vancouver Island Cryptococcus gattii
outbreak. Nature 437: 1360–1364.
Fraser JA, Hsueh YP, Findley KM & Heitman J (2007) Evolution
of the mating type locus: the basidiomycetes. Sex in Fungi:
Molecular Determination and Evolutionary Implications
(Heitman J, Kronstad JW, Taylor JW & Casselton LA, eds), pp.
19–34. ASM Press, Washington, DC.
Gadanho M & Sampaio JP (2002) Polyphasic taxonomy of the
basidiomycetous yeast genus Rhodotorula: R. glutinis sensu
stricto and R. dairenensis comb. nov. FEMS Yeast Res 2: 47–58.
Gadanho M, Sampaio JP & Spencer-Martins I (2001) Polyphasic
taxonomy of the basidiomycetous yeast genus
Rhodosporidium: R. azoricum sp. nov. Can J Microbiol 47:
213–221.
Gillissen B, Bergemann J, Sandmann C, Schroeer B, Bolker M &
Kahmann R (1992) A two-component regulatory system for
self/non-self recognition in Ustilago maydis. Cell 68: 647–657.
Giraud T, Yockteng R, Lopez-Villavicencio M, Refregier G &
Hood ME (2008) Mating system of the anther smut fungus
Microbotryum violaceum: selfing under heterothallism.
Eukaryot Cell 7: 765–775.
Goddard MR, Godfray HC & Burt A (2005) Sex increases the
efficacy of natural selection in experimental yeast populations.
Nature 434: 636–640.
Gueho E, Smith MT, de Hoog GS, Billon-Grand G, Christen R &
Batenburg-van der Vegte WH (1992) Contributions to a
revision of the genus Trichosporon. Antonie Van Leeuwenhoek
61: 289–316.
Gueho E, Midgley G & Guillot J (1996) The genus Malassezia
with description of four new species. Antonie Van Leeuwenhoek
69: 337–355.
Halliday CL, Bui T, Krockenberger M, Malik R, Ellis DH & Carter
DA (1999) Presence of alpha and a mating types in
environmental and clinical collections of Cryptococcus
neoformans var. gattii strains from Australia. J Clin Microbiol
37: 2920–2926.
Hawksworth DL (2001) The magnitude of fungal diversity: the
1.5 million species estimate revisited. Mycol Res 105:
1422–1432.
Hazen KC (1995) New and emerging yeast pathogens. Clin
Microbiol Rev 8: 462–478.
Heitman J (2006) Sexual reproduction and the evolution of
microbial pathogens. Curr Biol 16: R711–R725.
2009 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
c
174
Herskowitz I, Rine J & Strathern JN (1992) Mating type
determination and mating type interconversion in
Saccharomyces cerevisiae. The Molecular and Cellular Biology of
the Yeast Saccharomyces, Vol. 2: Gene Expression (Jones EW,
Pringle JR & Broach JR, eds), pp. 583–656. Cold Spring
Harbor Laboratory Press, New York.
Hibbett DS (2006) A phylogenetic overview of the
Agaricomycotina. Mycologia 98: 917–925.
Hibbett DS & Donoghue MJ (2001) Analysis of character
correlations among wood decay mechanisms, mating systems,
and substrate ranges in homobasidiomycetes. Syst Biol 50:
215–242.
Hibbett DS, Binder M, Bischoff JF et al. (2007) A higher-level
phylogenetic classification of the Fungi. Mycol Res 111:
509–547.
Ho CY, Adamson JG, Hodges RS & Smith M (1994)
Heterodimerization of the yeast MATa1 and MAT alpha 2
proteins is mediated by two leucine zipper-like coiled-coil
motifs. EMBO J 13: 1403–1413.
Hoang LM, Maguire JA, Doyle P, Fyfe M & Roscoe DL (2004)
Cryptococcus neoformans infections at Vancouver Hospital and
Health Sciences Centre (1997–2002): epidemiology,
microbiology and histopathology. J Med Microbiol 53:
935–940.
Hood ME (2002) Dimorphic mating type chromosomes in the
fungus Microbotryum violaceum. Genetics 160: 457–461.
Hood ME & Antonovics J (2000) Intratetrad mating,
heterozygosity, and the maintenance of deleterious alleles in
Microbotryum violaceum ( = Ustilago violacea). Heredity 85:
231–241.
Hull CM & Johnson AD (1999) Identification of a mating
type-like locus in the asexual pathogenic yeast Candida
albicans. Science 285: 1271–1275.
Hull CM, Raisner RM & Johnson AD (2000) Evidence for mating
of the ‘‘asexual’’ yeast Candida albicans in a mammalian host.
Science 289: 307–310.
Hull CM, Boily MJ & Heitman J (2005) Sex-specific
homeodomain proteins Sxi1alpha and Sxi2a coordinately
regulate sexual development in Cryptococcus neoformans.
Eukaryot Cell 4: 526–535.
Idnurm A, Walton FJ, Floyd A & Heitman J (2008) Identification
of the sex genes in an early diverged fungus. Nature 451:
193–196.
Ikeda R, Sugita T & Shinoda T (2000) Serological relationships
of Cryptococcus spp.: distribution of antigenic factors in
Cryptococcus and intraspecies diversity. J Clin Microbiol 38:
4021–4025.
Ikeda R, Sugita T, Jacobson ES & Shinoda T (2002) Laccase and
melanization in clinically important Cryptococcus species other
than Cryptococcus neoformans. J Clin Microbiol 40: 1214–1218.
Kahmann R & Kamper J (2004) Ustilago maydis: how its biology
relates to pathogenic development. New Phytol 164: 31–42.
Kamper J, Reichmann M, Romeis T, Bolker M & Kahmann R
(1995) Multiallelic recognition: nonself-dependent
2009 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
c
C.A. Morrow & J.A. Fraser
dimerization of the bE and bW homeodomain proteins in
Ustilago maydis. Cell 81: 73–83.
Khawcharoenporn T, Apisarnthanarak A & Mundy LM (2007)
Non-neoformans cryptococcal infections: a systematic review.
Infection 35: 51–58.
Kidd SE, Hagen F, Tscharke RL, Huynh M, Bartlett KH, Fyfe M,
Macdougall L, Boekhout T, Kwon-Chung KJ & Meyer W
(2004) A rare genotype of Cryptococcus gattii caused the
cryptococcosis outbreak on Vancouver Island (British
Columbia, Canada). P Natl Acad Sci USA 101: 17258–17263.
Kirk PM, Cannon PF, David JC & Stalpers JA (2001) Ainsworth
& Bisby’s Dictionary of the Fungi, 9th edn. CABI Publishing,
Wallingford.
Kordossis T, Avlami A, Velegraki A, Stefanou I, Georgakopoulos
G, Papalambrou C & Legakis NJ (1998) First report of
Cryptococcus laurentii meningitis and a fatal case of
Cryptococcus albidus cryptococcaemia in AIDS patients. Med
Mycol 36: 335–339.
Koufopanou V, Burt A & Taylor JW (1997) Concordance of gene
genealogies reveals reproductive isolation in the pathogenic
fungus Coccidioides immitis. P Natl Acad Sci USA 94:
5478–5482.
Krajden S, Summerbell RC, Kane J, Salkin IF, Kemna ME, Rinaldi
MG, Fuksa M, Spratt E, Rodrigues C & Choe J (1991)
Normally saprobic cryptococci isolated from Cryptococcus
neoformans infections. J Clin Microbiol 29: 1883–1887.
Krcmery Jr V, Mateicka F, Kunova A, Spanik S, Gyarfas J, Sycova Z
& Trupl J (1999) Hematogenous trichosporonosis in cancer
patients: report of 12 cases including 5 during prophylaxis
with itraconazole. Support Care Cancer 7: 39–43.
Kurjan J & Herskowitz I (1982) Structure of a yeast pheromone
gene (MF alpha): a putative alpha-factor precursor contains
four tandem copies of mature alpha-factor. Cell 30: 933–943.
Kurtzman CP (1973) Formation of hyphae and chlamydospores
by Cryptococcus laurentii. Mycologia 65: 388–395.
Kwon-Chung KJ (1975) A new genus, Filobasidiella, the perfect
state of Cryptococcus neoformans. Mycologia 67: 1197–1200.
Kwon-Chung KJ (1976) A new species of Filobasidiella, the sexual
state of Cryptococcus neoformans B and C serotypes. Mycologia
68: 943–946.
Kwon-Chung KJ & Bennett JE (1978) Distribution of alpha and a
mating types of Cryptococcus neoformans among natural and
clinical isolates. Am J Epidemiol 108: 337–340.
Kwon-Chung KJ, Edman JC & Wickes BL (1992) Genetic
association of mating types and virulence in Cryptococcus
neoformans. Infect Immun 60: 602–605.
Lagrou K, Massonet C, Theunissen K, Meersseman W, Lontie M,
Verbeken E, Van Eldere J & Maertens J (2005) Fatal pulmonary
infection in a leukaemic patient caused by Hormographiella
aspergillata. J Med Microbiol 54: 685–688.
Leberer E, Thomas DY & Whiteway M (1997) Pheromone
signalling and polarized morphogenesis in yeast. Curr Opin
Genet Dev 7: 59–66.
Lee N, Bakkeren G, Wong K, Sherwood JE & Kronstad JW (1999)
The mating type and pathogenicity locus of the fungus
FEMS Yeast Res 9 (2009) 161–177
175
Sexual reproduction in pathogenic yeasts
Ustilago hordei spans a 500-kb region. P Natl Acad Sci USA 96:
15026–15031.
Lengeler KB, Wang P, Cox GM, Perfect JR & Heitman J (2000)
Identification of the MATa mating type locus of Cryptococcus
neoformans reveals a serotype A MATa strain thought to have
been extinct. P Natl Acad Sci USA 97: 14455–14460.
Lengeler KB, Fox DS, Fraser JA, Allen A, Forrester K, Dietrich FS
& Heitman J (2002) mating type locus of Cryptococcus
neoformans: a step in the evolution of sex chromosomes.
Eukaryot Cell 1: 704–718.
Lin X, Hull CM & Heitman J (2005) Sexual reproduction between
partners of the same mating type in Cryptococcus neoformans.
Nature 434: 1017–1021.
Litvintseva AP, Marra RE, Nielsen K, Heitman J, Vilgalys R &
Mitchell TG (2003) Evidence of sexual recombination among
Cryptococcus neoformans serotype A isolates in sub-Saharan
Africa. Eukaryot Cell 2: 1162–1168.
Litvintseva AP, Thakur R, Vilgalys R & Mitchell TG (2005)
Multilocus sequence typing reveals three genetically distinct
subpopulations of Cryptococcus neoformans var. grubii
(serotype A), including a unique population in Botswana.
Genetics 172: 2223–2238.
Lyman CA, Devi SJ, Nathanson J, Frasch CE, Pizzo PA &
Walsh TJ (1995) Detection and quantitation of the
glucuronoxylomannan-like polysaccharide antigen from
clinical and nonclinical isolates of Trichosporon beigelii and
implications for pathogenicity. J Clin Microbiol 33: 126–130.
Madhani HD & Fink GR (1998) The control of filamentous
differentiation and virulence in fungi. Trends Cell Biol 8:
348–353.
Magee BB & Magee PT (2000) Induction of mating in Candida
albicans by construction of MTLa and MTLa strains. Science
289: 310–313.
Martinez C, Roux C, Jauneau A & Dargent R (2002) The
biological cycle of Sporisorium reilianum f.sp. zeae: an
overview using microscopy. Mycologia 94: 505–514.
Middelhoven WJ, Scorzetti G & Fell JW (2004) Systematics of the
anamorphic basidiomycetous yeast genus Trichosporon
Behrend with the description of five novel species:
Trichosporon vadense, T. smithiae, T. dehoogii, T. scarabaeorum
and T. gamsii. Int J Syst Evol Micr 54: 975–986.
Mitchell TG (2005) Kingdom Fungi: fungal phylogeny and
systematics. Topley & Wilson’s Microbiology and Microbial
Infections. Vol. 5, Medical Mycology, 10th edn (Merz WG & Hay
RJ, eds), pp. 43–68. Hodder Arnold, London.
Moore M, Russell WO & Sachs E (1946) Chronic leptomeningitis
and ependymitis caused by Ustilago, probably U. zeae (corn
smut) – ustilagomycosis, the 2nd reported instance of human
infection. Am J Pathol 22: 761–777.
Muller P, Weinzierl G, Brachmann A, Feldbrugge M & Kahmann
R (2003) Mating and pathogenic development of the smut
fungus Ustilago maydis are regulated by one mitogen-activated
protein kinase cascade. Eukaryot Cell 2: 1187–1199.
Nadal M, Garcia-Pedrajas MD & Gold SE (2008) Dimorphism in
fungal plant pathogens. FEMS Microbiol Lett 284: 127–134.
FEMS Yeast Res 9 (2009) 161–177
Neofytos D, Horn D & De Simone Jr JA (2007) Rhodotorula
mucilaginosa catheter-related fungemia in a patient with sickle
cell disease: case presentation and literature review. South Med
J 100: 198–200.
Nielsen K & Heitman J (2007) Sex and virulence of human
pathogenic fungi. Adv Genet 57: 143–173.
Nielsen K, Cox GM, Wang P, Toffaletti DL, Perfect JR & Heitman
J (2003) Sexual cycle of Cryptococcus neoformans var. grubii
and virulence of congenic a and alpha isolates. Infect Immun
71: 4831–4841.
Nielsen K, Cox GM, Litvintseva AP et al. (2005) Cryptococcus
neoformans alpha strains preferentially disseminate to the
central nervous system during coinfection. Infect Immun 73:
4922–4933.
Nielsen K, De Obaldia AL & Heitman J (2007) Cryptococcus
neoformans mates on pigeon guano: implications for the
realized ecological niche and globalization. Eukaryot Cell 6:
949–959.
O’Shea SF, Chaure PT, Halsall JR, Olesnicky NS, Leibbrandt A,
Connerton IF & Casselton LA (1998) A large pheromone and
receptor gene complex determines multiple B mating type
specificities in Coprinus cinereus. Genetics 148: 1081–1090.
Otto SP & Nuismer SL (2004) Species interactions and the
evolution of sex. Science 304: 1018–1020.
Paoletti M, Rydholm C, Schwier EU, Anderson MJ, Szakacs G,
Lutzoni F, Debeaupuis JP, Latge JP, Denning DW & Dyer PS
(2005) Evidence for sexuality in the opportunistic fungal
pathogen Aspergillus fumigatus. Curr Biol 15: 1242–1248.
Patel R, Roberts GD, Kelly DG & Walker RC (1995) Central
venous catheter infection due to Ustilago species. Clin Infect
Dis 21: 1043–1044.
Plazas J, Portilla J, Boix V & Perez-Mateo M (1994)
Sporobolomyces salmonicolor lymphadenitis in an AIDS
patient. Pathogen or passenger? AIDS 8: 387–388.
Powell KE, Dahl BA, Weeks RJ & Tosh FE (1972) Airborne
Cryptococcus neoformans: particles from pigeon excreta
compatible with alveolar deposition. J Infect Dis 125: 412–415.
Preininger T (1937) Dermatomycosis that is conditional upon
maize mildew (Ustilago maydis). Arch Dermatol Syph 176:
109–113.
Raper J (1966) Genetics of Sexuality in Higher Fungi. Ronald Press
Company, New York.
Rihs JD, Padhye AA & Good CB (1996) Brain abscess caused by
Schizophyllum commune: an emerging basidiomycete
pathogen. J Clin Microbiol 34: 1628–1632.
Ruiz A & Bulmer GS (1981) Particle size of airborne Cryptococcus
neoformans in a tower. Appl Environ Microbiol 41: 1225–1229.
Sampaio JP, Gadanho M, Santos S, Duarte FL, Pais C, Fonseca A
& Fell JW (2001) Polyphasic taxonomy of the basidiomycetous
yeast genus Rhodosporidium: Rhodosporidium kratochvilovae
and related anamorphic species. Int J Syst Evol Micr 51:
687–697.
Saul N, Krockenberger M & Carter D (2008) Evidence of
recombination in mixed-mating type and alpha-only
2009 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
c
176
populations of Cryptococcus gattii sourced from single
eucalyptus tree hollows. Eukaryot Cell 7: 727–734.
Schirawski J, Heinze B, Wagenknecht M & Kahmann R (2005)
Mating type loci of Sporisorium reilianum: novel pattern with
three a and multiple b specificities. Eukaryot Cell 4: 1317–1327.
Schulz B, Banuett F, Dahl M, Schlesinger R, Schafer W, Martin T,
Herskowitz I & Kahmann R (1990) The b alleles of U. maydis,
whose combinations program pathogenic development, code
for polypeptides containing a homeodomain-related motif.
Cell 60: 295–306.
Seifert K & Gams W (2001) The taxonomy of anamorphic fungi.
The Mycota VII, Part A. Systematics and Evolution
(McLaughlin DJ, McLaughlin E & Lemke PA, eds), pp.
307–347. Springer-Verlag, Berlin.
Serena C, Pastor FJ, Ortoneda M, Capilla J, Nolard N & Guarro J
(2004) In vitro antifungal susceptibilities of uncommon
basidiomycetous yeasts. Antimicrob Agents Ch 48: 2724–2726.
Sexton AC & Howlett BJ (2006) Parallels in fungal pathogenesis
on plant and animal hosts. Eukaryot Cell 5: 1941–1949.
Sharma V, Shankar J & Kotamarthi V (2006) Endogeneous
endophthalmitis caused by Sporobolomyces salmonicolor. Eye
20: 945–946.
Shifrine M & Marr AG (1963) Requirement of fatty acids by
Pityrosporum ovale. J Gen Microbiol 32: 263–270.
Shivas RG & Hyde KD (1997) Biodiversity of plant pathogenic
fungi in the tropics. Biodiversity of Tropical Microfungi (Hyde
KD, ed), pp. 47–56. Hong Kong University Press, Hong Kong.
Spellig T, Bolker M, Lottspeich F, Frank RW & Kahmann R (1994)
Pheromones trigger filamentous growth in Ustilago maydis.
EMBO J 13: 1620–1627.
Stankis MM, Specht CA, Yang H, Giasson L, Ullrich RC &
Novotny CP (1992) The A alpha mating locus of
Schizophyllum commune encodes two dissimilar multiallelic
homeodomain proteins. P Natl Acad Sci USA 89: 7169–7173.
Steinberg G (2007) Hyphal growth: a tale of motors, lipids, and
the Spitzenkorper. Eukaryot Cell 6: 351–360.
Sugita T, Takashima M, Ikeda R, Nakase T & Shinoda T (2000)
Intraspecies diversity of Cryptococcus laurentii as revealed by
sequences of internal transcribed spacer regions and 28S rRNA
gene and taxonomic position of C. laurentii clinical isolates.
J Clin Microbiol 38: 1468–1471.
Sugita T, Takashima M, Poonwan N et al. (2003) The first
isolation of ustilaginomycetous anamorphic yeasts,
Pseudozyma species, from patients’ blood and a description of
two new species: P. parantarctica and P. thailandica. Microbiol
Immunol 47: 183–190.
Sukroongreung S, Kitiniyom K, Nilakul C & Tantimavanich S
(1998) Pathogenicity of basidiospores of Filobasidiella
neoformans var. neoformans. Med Mycol 36: 419–424.
Swann E, Frieders E & McLaughlin D (2001) Urediniomycetes.
The Mycota VII, Part B. Systematics and Evolution (McLaughlin
DJ, McLaughlin EG & Lemke PA, eds), pp. 37–56. SpringerVerlag, Berlin.
Takashima M, Sugita T, Shinoda T & Nakase T (2003) Three new
combinations from the Cryptococcus laurentii complex:
2009 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
c
C.A. Morrow & J.A. Fraser
Cryptococcus aureus, Cryptococcus carnescens and Cryptococcus
peneaus. Int J Syst Evol Micr 53: 1187–1194.
Tashiro T, Nagai H, Kamberi P, Goto Y, Kikuchi H, Nasu M &
Akizuki S (1994) Disseminated Trichosporon beigelii infection
in patients with malignant diseases: immunohistochemical
study and review. Eur J Clin Microbiol 13: 218–224.
Tashiro T, Nagai H, Nagaoka H, Goto Y, Kamberi P & Nasu M
(1995) Trichosporon beigelii pneumonia in patients with
hematologic malignancies. Chest 108: 190–195.
Thakur K, Singh G, Agarwal S & Rani L (2007) Meningitis caused
by Rhodotorula rubra in a human immunodeficiency virus
infected patient. Indian J Med Microbiol 25: 166–168.
Thomas DS, Ingham E, Bojar RA & Holland KT (2008) In vitro
modulation of human keratinocyte pro- and antiinflammatory cytokine production by the capsule of
Malassezia species. FEMS Immunol Med Mic 54: 203–214.
Trilles L, Lazera MS, Wanke B, Oliveira RV, Barbosa GG,
Nishikawa MM, Morales BP & Meyer W (2008) Regional
pattern of the molecular types of Cryptococcus neoformans and
Cryptococcus gattii in Brazil. Mem I Oswaldo Cruz 103:
455–462.
Tuon FF & Costa SF (2008) Rhodotorula infection. A systematic
review of 128 cases from literature. Rev Iberoam Micol 25:
135–140.
Tuon FF, de Almeida GM & Costa SF (2007) Central venous
catheter-associated fungemia due to Rhodotorula spp. – a
systematic review. Med Mycol 45: 441–447.
Tymon AM, Kues U, Richardson WV & Casselton LA (1992) A
fungal mating type protein that regulates sexual and asexual
development contains a POU-related domain. EMBO J 11:
1805–1813.
Vaillancourt LJ, Raudaskoski M, Specht CA & Raper CA (1997)
Multiple genes encoding pheromones and a pheromone
receptor define the B beta 1 mating type specificity in
Schizophyllum commune. Genetics 146: 541–551.
Valerio E, Gadanho M & Sampaio JP (2008a) Reappraisal of the
Sporobolomyces roseus species complex and description of
Sporidiobolus metaroseus sp. nov. Int J Syst Evol Micr 58:
736–741.
Valerio E, Gadanho M & Sampaio JP (2008b) Sporidiobolus
johnsonii and Sporidiobolus salmonicolor revisited. Mycol Prog
7: 125–131.
Van der Walt JP (1970) The perfect and imperfect states of
Sporobolomyces salmonicolor. Antonie Van Leeuwenhoek 36:
49–55.
Vanky K (1987) Illustrated Genera of Smut Fungi. Gustav Fischer,
Stuttgart.
Walsh TJ, Lee JW, Melcher GP, Navarro E, Bacher J, Callender D,
Reed KD, Wu T, Lopez-Berestein G & Pizzo PA (1992)
Experimental Trichosporon infection in persistently
granulocytopenic rabbits: implications for pathogenesis,
diagnosis, and treatment of an emerging opportunistic
mycosis. J Infect Dis 166: 121–133.
Walsh TJ, Groll A, Hiemenz J, Fleming R, Roilides E & Anaissie E
(2004) Infections due to emerging and uncommon medically
FEMS Yeast Res 9 (2009) 161–177
177
Sexual reproduction in pathogenic yeasts
important fungal pathogens. Clin Microbiol Infect 10 (suppl 1):
48–66.
Wang P, Nichols CB, Lengeler KB, Cardenas ME, Cox GM, Perfect
JR & Heitman J (2002) mating type-specific and nonspecific
PAK kinases play shared and divergent roles in Cryptococcus
neoformans. Eukaryot Cell 1: 257–272.
Wells K & Bandoni RJ (2001) Heterobasidiomycetes. The
Mycota VII, Part B. Systematics and Evolution (McLaughlin DJ,
McLaughlin EG & Lemke PA, eds), pp. 85–120. SpringerVerlag, Berlin.
Wendland J, Vaillancourt LJ, Hegner J, Lengeler KB, Laddison KJ,
Specht CA, Raper CA & Kothe E (1995) The mating type locus
B alpha 1 of Schizophyllum commune contains a pheromone
receptor gene and putative pheromone genes. EMBO J 14:
5271–5278.
Whitehouse HLK (1949) Multiple allelomorph heterothallism in
the fungi. New Phytol 48: 212–244.
Wickes BL, Mayorga ME, Edman U & Edman JC (1996)
Dimorphism and haploid fruiting in Cryptococcus neoformans:
association with the alpha-mating type. P Natl Acad Sci USA
93: 7327–7331.
FEMS Yeast Res 9 (2009) 161–177
Woo PC, Chong KT, Tse H, Cai JJ, Lau CC, Zhou AC,
Lau SK & Yuen KY (2006) Genomic and experimental
evidence for a potential sexual cycle in the pathogenic thermal
dimorphic fungus Penicillium marneffei. FEBS Lett 580:
3409–3416.
Xu J, Saunders CW, Hu P et al. (2007) Dandruff-associated
Malassezia genomes reveal convergent and divergent virulence
traits shared with plant and human fungal pathogens. P Natl
Acad Sci USA 104: 18730–18735.
Xue C, Tada Y, Dong X & Heitman J (2007) The human fungal
pathogen Cryptococcus can complete its sexual cycle during a
pathogenic association with plants. Cell Host Microbe 1:
263–273.
Yockteng R, Marthey S, Chiapello H, Gendrault A, Hood ME,
Rodolphe F, Devier B, Wincker P, Dossat C & Giraud T (2007)
Expressed sequences tags of the anther smut fungus,
Microbotryum violaceum, identify mating and pathogenicity
genes. BMC Genomics 8: 272.
Zimmer BL, Hempel HO & Goodman NL (1984) Pathogenicity
of the basidiospores of Filobasidiella neoformans.
Mycopathologia 85: 149–153.
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