Fantastic Yeasts and Where To Find Them: The Hidden Diversity of Dimorphic Fungal Pathogens

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Fantastic yeasts and where to find them: the hidden


diversity of dimorphic fungal pathogens
Marley C Caballero Van Dyke1, Marcus M Teixeira1,2 and
Bridget M Barker1

Dimorphic fungal pathogens are a significant cause of human (see current phylogenetic representation of these species
disease worldwide. Notably, the dimorphic fungal pathogens in Figure 1). These fungal organisms are known to be
within the order Onygenales are considered primary dimorphic fungal pathogens, which emerged around
pathogens, causing disease in healthy hosts. Current changes 150 MYA [1], and are capable of growth in the environment
in taxonomy are underway due to advances in molecular on at a wide range of temperatures and in the human host at
phylogenetics, population genetics, and new emerging 37 C [2]. Dimorphic fungal pathogens in the order Ony-
dimorphic fungal pathogens causing human disease. In this genales are known as primary pulmonary pathogens that
review, we highlight evolutionary relationships of dimorphic cause disease in immunocompetent individuals with over
fungal pathogens that cause human disease within the order 650 000 new infections occurring each year in the United
Onygenales and provide rationale to support increased States [3]. These fungi generally live as saprobes producing
investment in studies understanding the evolutionary filamentous mycelium and under certain environmental
relationships of these pathogens to improve rapid diagnostics, circumstances produce asexual conidia (e.g. arthroconidia,
help identify mechanisms of antifungal resistance, understand blastoconidia, etc.). Upon the inhalation of conidia by a
adaptation to human host, and factors associated with susceptible host, these fungi switch into their parasitic form
virulence. (e.g. yeasts, spherules, adiaspores, etc.) (Figure 2) and
live as endozoans, maintaining an active or inactive stage
Addresses
1
within host granulomas. These fungi may return to the
Pathogen and Microbiome Institute, Northern Arizona University, environment upon host death transforming into conidia-
Flagstaff, AZ, United States
2
Faculty of Medicine, University of Brası́lia, Brası́lia-DF, Brazil
producing mycelia [4].

Corresponding author: Barker, Bridget M (bridget.barker@nau.edu)


Defining pathogenic fungal species based on morpholog-
ical characteristics poses many challenges because not all
Current Opinion in Microbiology 2019, 52:55–63 fungi are cultivable in media, not all fungal pathogens
This review comes from a themed issue on Host–microbe interac- easily produce sexual fruiting bodies, and some fungi are
tions: fungi homothallic (self-fertile) and therefore will not exhibit a
Edited by Chad A Rappleye and Duncan Wilson detectable inheritance pattern. Before the genomic era,
Genealogical Concordance for Phylogenetic Species Rec-
For a complete overview see the Issue and the Editorial
ognition (GCPSR) was the method of choice for defining
Available online 7th June 2019
species boundaries within Onygenales and other fungi
https://doi.org/10.1016/j.mib.2019.05.002 [5]. This approach is based on Multi Locus Sequencing
1369-5274/ã 2019 Elsevier Ltd. All rights reserved. Type (MLST) to assess sequence variation of conserved
housekeeping genes or other neutral loci. The genetic
background of centennial species (i.e. Coccidioides immitis,
Paracoccidioides brasiliensis, Histoplasma capsulatum, and
Blastomyces dermatitidis) were resolved leading to new
phylogenetically isolated species and new dimorphic
fungal pathogens were described (e.g. Emergomyces) [5].
Introduction
The fungal kingdom contains millions of ubiquitous fungal
species, and most pose no or trivial direct threat to human Advances in molecular phylogenetics and population
health. However, a handful of species can cause devastating genetics based on genomic science have significantly
disease in both immunocompetent and immunocompro- improved our ability to accurately define fungal species
mised individuals. Although plants can also be affected by limits and hybridization events that shaped the Onygen-
fungal pathogens, this review highlights a distinct group of alean clade [6]. Sequencing the genomes of Onygenalean
dimorphic fungal pathogens that cause disease in humans. fungal pathogens also provides information to better
This specific group of fungi that cause systemic infections is understand shared and unique adaptive traits between
nested within the order Onygenales (Eurotiomycetes, species complexes, such as metabolism, mating patterns,
Ascomycota) which include Coccidioides, Histoplasma, gene gain or loss, and chromosomal variations that may be
Blastomyces, Paracoccidioides, Emmonsia, and Emergomyces associated with infection and disease progression [1].

www.sciencedirect.com Current Opinion in Microbiology 2019, 52:55–63


56 Host–microbe interactions: fungi

Figure 1

Adiaspore-forming
species

Ajellomycetaceae
Emmonsia crescens
Emmonsia sola

Blastomyces dermatitidis
Blastomyces gilchristii
Blastomyces helicus
Blastomyces percursus
Blastomyces silverae
Blastomyces parvus

Histoplasma capsulatum (Panama)


Histoplasma mississippiense
Histoplasma ohiense
Yeast-forming
3/13 MYA Histoplasma suramericanum (RJ, LAm A1, LAm A2)
species Histoplasma sp. (Eurasia, BAC1, Netherlands,
Africa, Australia, LAm B1, LAm B2)
Emergomyces africanus
Emergomyces canadensis
Emergomyces europaeus
Emergomyces orientalis
Emergomyces pasteurianus

Paracoccidioides lutzii
Paracoccidioides brasiliensis (S1a, S1b)
Paracoccidioides americana
22.5/33 MYA Paracoccidioides restrepiensis
Spherule-forming
species
Paracoccidioides venezuelensis

Helicocarpus griseus

Polytolypa hystricis

Emmonsiellopsis terrestris
Emmonsiellopsis coralliformis

Arthrodermataceae

Coccidioides immitis
Coccidioides posadasii
5.1-12.8 MYA

Amauroascus mutatus
Amauroascus niger
Byssoonygena ceratinophila
Chrysosporium queenslandicum

Ascosphaeraceae

Eurotiales

Current Opinion in Microbiology

Phylogenetic representation of the evolutionary trajectory of the order onygenales.


The branch distribution is based on MLST tree (rPB2, TUB2, TEF3, ITS, and LSU), whole genome phylogentic trees, and node calibrations
previously published (4200 core genes) [6,61,71]. Solid black branches are concordant between both phylogenetic studies and dotted branches
are due to uncertainty regarding the true phylogenomic position of Emmonsiellopsis. The solid grey branch represents the outgroup formed by
Eurotiales species. The solid red square represents the most common ancestor of Onygenales that emerged around 150 MYA and black ellipsis
are nodes distinguishing each lineage. Red nodes represent the age of divergence of each species complex previously analyzed [6,12,37,64].
Blastomyces parvus (*) and Emergomyces pasteurianus (#) were previously known as Emmonsia crescens and E. pasteuriana, respectively. The
forms of pathogenic structures among the Onygenales are displayed along the tree.

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Dimorphic fungi Van Dyke, Teixeira and Barker 57

Figure 2

Environment Host (37°C)

Blastomyces

Coccidioides

Emmonsia

Emergomyces

Histoplasma

Paracoccidioides

Current Opinion in Microbiology

Morphological shifts of Onygenalean fungi.


The simple cartoons for each dimorphic Onygenales are shown. In the environment, each of these species is in its hyphal/mycelial form with oval
or circular shapes representing the vegetative conidia. In the case of Blastomyces, Emergomyces, Histoplasma, and Paracoccidioides in the host,
these switch to yeast-phase with some characteristic differences. Blastomyces yeast cells display a broad bud neck; Emergomyces have yeast
cells with unipolar or bipolar budding at narrow base; Paracoccidioides have yeast that can be multibudded. In the host, Coccidioides switches to
endosporulating spherules which then ruptures to release endospores. Emmonsia switches to an adiaspore (non-endosporulating spherule).
(Illustration created with BioRender).

Additionally, comparative genomic analyses between new estimates suggest 350 000 new infections are occur-
pathogenic and non-pathogenic closely related fungal ring each year in the United States [T Chiller, abstract in
species provide evidence of recently diverged species Vaccine Strategies for Endemic Fungal Pathogens,
and adaptation to mammalian hosts. This review high- NIAID, Rockville, MD, March 2019].
lights studies on the phylogenetics and evolution of
dimorphic fungal pathogens, and provides insight into Recently, studies have combined phylogenetic meta-
current taxonomy, pathogenicity potential, recombina- analysis and population genetics to identify at least six
tion patterns, and gene gain/loss within species distinct populations within the two genetically diverse
complexes and across different populations and species. species, C. immitis and C. posadasii [11,12]. C. immitis is
restricted to Northwestern Mexico, California, and
Coccidioidomycosis Washington. In contrast, C. posadasii is widely distributed
Coccidioidomycosis or San Joaquin ‘Valley Fever’ is a in the Americas ranging from the Sonora and Chihuahua
fungal infection caused by two Onygenaceae species, deserts (including Arizona, Texas, New Mexico, and
C. immitis and Coccidioides posadasii (Figure 1). Coccidioi- Northeast Mexico) to Central and South America. The
domycosis occurs most notably in California and Arizona, current understanding of population structure within both
which together account for a majority of reported cases in species complexes has been constantly revisited over the
the United States (Figure 3) [7]. Outside the United past 20 years. On the basis of multiple markers, these
States, there have been cases in the Northern region of studies reveal three populations within C. immitis (San
Mexico [8], Central America, and arid regions of South Joaquin/Central Valley California, Southern California/
America such as Argentina, Brazil, Paraguay, and Vene- Mexico, and Washington) and three populations within
zuela [9]. Although most cases are asymptomatic (60%), C. posadasii (Arizona, Texas/Mexico/South America and
the literature states there are about 150 000 new Guatemala) (Figure 3) [12–14]. Although these
infections each year in the United States [10]; however, populations are genetically different, limited gene flow

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58 Host–microbe interactions: fungi

Figure 3

Coccidioidomycosis

Blastomycosis
Emmonsia/Emergomyces

Histoplasmosis

Paracoccidoidomycosis

Current Opinion in Microbiology

Estimated global distribution of Onygenales that cause human disease.


These geographical locations for endemic sites of Onygenales are an estimate. Histoplasmosis has a worldwide distribution and the map depicts
known endemic regions. This map has been adapted from Ref. [32, CDC; https://www.cdc.gov/features/fungalinfections/] with distribution of
infections caused by Emergomyces ( ) and Blastomyces ( ) adapted from Ref. [53]. (Illustration created with BioRender).

does occur and few phenotypical differences have been virulence factor in a maize pathogen, to be important
identified between species [14]. for virulence in Coccidioides [18]. The deletion of the
CPS1 gene in C. posadasii resulted in complete attenu-
Both species of Coccidioides share the same asexual life ation of disease in a murine model [19]. Studies utiliz-
cycle switching between saprobic and parasitic life ing microarray gene expression analysis show 2208
cycles. Despite the divergence of these two species, C. immitis genes were differently expressed in spherules
about 5.1 MYA [14], gene exchange between C. immitis compared to mycelia form [20]. Additional studies by
and C. posadasii is thought to occur. Recent studies Whiston et al. using RNA-Seq demonstrated an upre-
utilized a large sample of genomes from each species to gulation of 1880 genes in the spherule stage of
quantify the magnitude of gene exchange whereby Coccidioides [21]. Collectively, these studies demon-
identifying genomic regions that have crossed from strated similar gene expression profiles with differen-
one species to another [15]. These studies indicated tially expressed genes associated with defense against
that introgressions have occurred within species at low oxidative stress, cell wall remodeling, lipid metabolism,
frequencies establishing that admixture is either rare or and genes associated with virulence factors. Previous
deleterious. reports focusing on dermatophytes demonstrated the
expansion of proteins related to the peptidoglycan
Importantly, studies conducted on dimorphic fungi to binding domain LysM which has been shown to be
understand the underlying mechanisms of morphologi- involved in fungal immunity [22]. However, recent
cal transition between environmental and pathogenic studies compared Coccidioides genomes to other non-
forms aim to uncover virulence-defining genes and find pathogenic Onygenaceae species and demonstrated a
potential new drug targets. Studies conducted by Hung contraction in LysM gene families in Coccidioides
et al. determined a gene that encodes for a glycoprotein species [23]. The authors of this study express their
present on the cell surface, spherule outer wall glyco- opinion that LysM gene families may be more immu-
protein (SOWgp), that contributes to virulence by noreactive demonstrating the disadvantage of the
functioning as both an adhesin and a host immune presence of these gene families in pathogenic fungi,
response modulator [16,17]. Additional studies which could explain the gene family contraction of
determined the CPS1 gene, homologous to an identified LysM-containing genes in Coccidioides [23].

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Dimorphic fungi Van Dyke, Teixeira and Barker 59

Histoplasmosis localized on the cell wall of certain strains of Histoplasma


H. capsulatum sensu lato is a pathogenic fungus that causes [37]. Additionally, studies demonstrated the role of YPS3
histoplasmosis, a life-threatening systemic mycosis [24]. on mammalian virulence in vivo using the RNA-mediated
Histoplasmosis is known to be one of the most common interference (RNAi) strategy whereby silencing led to
pulmonary fungal diseases in the United States [25]; decreased fungal burden compared to wild type infection
however, cases of histoplasmosis have a worldwide [38]. Another important virulence factor in Histoplasma
distribution occurring in both temperate and tropical pathogenicity includes Calcium-binding protein, CBP,
regions (Figure 3) [26–30]. The fungus is usually found where studies demonstrated deletion of CBP1 allowed
in sites enriched with bird or bat guano that allows the for rapid clearance of yeast cells from the lungs of infected
development of the aerial mycelial containing infectious mice [39]. Furthermore, studies determined the
airborne microconidia (Figure 2). production of siderophores as a virulence factor in
Histoplasma [40,41]. Disruption of the SID1 gene, an
Historically, three distinct varieties of Histoplasma were enzyme important for siderophore production, resulted
determined based on morphology and clinical aspects: in a growth defect in vitro and attenuation of infection in
New World human pathogen (H. capsulatum var. the murine model of histoplasmosis.
capsulatum), African human pathogen (var. duboisii), and
Old World horse pathogen (var. farciminosum) [31,32]. Other Onygenales
GCPSR studies conducted by Kasuga et al. demonstrated Additional human fungal pathogens from the Onygenales
that H. capsulatum contains at least eight phylogenetic order that belong to the family Ajellomycetaceae include
species: LAm A and LAm B (primarily from Latin Amer- Blastomyces, Paracoccidioides, Emmonsia, and Emergomyces
ica), NAm 1 and NAm 2 (restricted to North America), (Figure 1). The infections caused by these fungi range
Eurasian (Egypt, India, China, Thailand, and England), from asymptomatic to mild pneumonia, acute respiratory
Netherlands, Africa, and Australia [27]. The three distress, and dissemination to multiple organ systems
historical Histoplasma varieties were found in multiple which is often fatal, especially in immunocompromised
monophyletic lineages and were therefore invalidated. individuals [42–44].
Additionally, eleven species-level clades within
H. capsultum, were identified. The former LAm A and Blastomyces
LAm B species were further split into five different Blastomycosis is a lung infection caused by the etiological
genetic clusters as follows: RJ, LAm A1, LAm A2, agent Blastomyces spp., endemic to areas of North America
LAm B1, and LAm B2 [29]. Additionally, a new phylo- including Ohio and Mississippi river valley, the Great
genetic species, BAC-1 (Mexico), and four different Lakes, and the St. Lawrence River (Figure 3) [45,46].
monophyletic lineages from Brazil (BR1–4) were identi- Until recently, B. dermatitidis was believed to be the only
fied (Figure 1) [29]. Recently, whole genome sequencing species; however, studies utilizing population genetic
was used to compare 30 Histoplasma isolates demonstrat- analysis defined two different species: B. dermatitidis
ing H. capsulatum is composed of at least five groups [33] and Blastomyces gilchristii (Figure 1) [47–49]. B. dermatitidis
and four different species were proposed as follows: and B. gilchristii are the most common agents of
Histoplasma sensu stricto Darling (Panama), Histoplasma blastomycosis; these species diverged about 1.9 MYA
mississippiense (NAm 1), Histoplasma ohiense (NAm 2), and and studies suggest that additional cryptic populations/
Histoplasma suramericanum (LAm A) (Figure 1). The species exist [47]. Studies using deep comparative
authors also suggest hybridization and gene flow have genomic analysis revealed a large genome size for both
occurred between these cryptic species, but very species, B. dermatitidis at 66.6 Mb for the ER-3 stain to
infrequently, thus species boundaries are robust even 75.4 Mb for the B. gilchristii SLH14081 strain, which is
in sympatry [33]. H. ohiense and H. mississippiense were nearly double the size of other Onygenales [50]. Further-
further examined to determine the possibility of gene more, these studies show evidence that these genomes
exchange [34]. This study demonstrated recent comprise large isochore-like regions with low GC content.
hybridization between two strains of each species, Recent studies have revealed two new distinct species:
H. mississippiense and H. ohiense genomic reference strains, Blastomyces helicus (formerly Emmonsia helica) and
WU24 and G217B. With shared overlapping geographic Blastomyces percursus (formerly Emmonsia) (Figure 1)
boundaries of Histoplasma species, this study [51,52]. Therefore, infections due to Blastomyces are
demonstrates the potential for new hybrids of Histoplasma occurring outside the United States demonstrating the
in the future. underappreciation of the geographical distribution of this
organism (Figure 3) [53].
Studies utilizing H. capsulatum demonstrated a group of
important genes conserved for the dimorphism of other Previous studies have demonstrated BAD1 to be a virulence
pathogenic Onygenales: Required for Yeast Phase genes factor in Blastomyces where a knockout strain was shown to be
or RYP 1–4 [35,36]. A yeast phase-specific gene, YPS3, avirulent in mice [54]. Furthermore, studies demonstrated
was determined to encode a protein that is secreted and that expression of BAD1 was yeast-phase-specific in both

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60 Host–microbe interactions: fungi

B. dermatitidis and H. capsulatum demonstrating a common cells compared to other barrel-shaped conidia produced
mechanism between dimorphic fungal pathogens and the by Paracoccidioides species [65]. P. brasiliensis is the most
expression of yeast-phase-specific genes [55]. Additional dispersed species and comprises two populations, S1a and
studies found dimorphism-regulating kinase, DRK1, to be S1b, which have been found to overlap geographically in
required for phase transition from mold to yeast in Southeast Brazil, Argentina and Paraguay [66,67].
H. capsulatum and B. dermatitidis; thereby, functioning as a Paracoccidioides americana, formerly PS2, is the rarest
global regulator of both dimorphism and virulence [56]. species associated with cases reported in states of Brazil,
São Paulo, Minas Gerais, and Rio de Janeiro (Southeast
Emmonsia and Emergomyces Brazil), as well as in Venezuela [68,69]. Two other
Emmonsia is a genus that until recently was thought to species, Paracoccidioides venezuelensis (former PS4) and
cause adiapiromycosis, a pulmonary infection common in Paracoccidioides restrepiensis (former PS3), are geographi-
small mammals and rarely associated with human cally restricted to Venezuela and Colombia, respectively
infections and caused by two species: Emmonsia crescens [67,70]. Sequencing the genomes of both P. brasiliensis
and Emmonsia parva [51,57–59]. The pathogenic phase and P. lutzii was completed and comparison to other
of E. crescens is characterized by adiaspore (non- dimorphic fungal pathogens helped elucidate the
endosporulating spherule) production, whereas yeast-like divergence both within the Paracoccidioides lineage and
forms are recognized in infection due to E. parva. A among other dimorphic fungal species [71]. These studies
recent emergence of infections to Emmonsia in HIV- found expansions of the fungal-specific kinases family
positive patients in South Africa suggests that Emmonsia FunK1 and loss of genes involved in carbohydrate
is one of the most common causes of endemic mycosis metabolism while retaining Onygenales-specific
in that region (Figure 3) [60,61]. These proteases which highlights how Paracoccidioides may have
infections prompted phylogenetic studies which adapted to the human host.
proposed a new species: Emmonsia pasteuriana [60]. Addi-
tionally, recent MLST analysis of 5 loci showed E. crescens Comparative strategies across Onygenales
to be grouped on a single branch while E. parva is closely Dimorphic Onygenales demonstrate mostly mycelia to
related to Blastomyces species and was therefore re- yeast-phase transitions when introduced to a host or
classified as B. parvus because this species produces yeast temperature change (37 C); however, Emmonsia and
in its pathogenic form (Figure 1) [51]. Dukik et al. Coccidioides demonstrate unique structures when
proposed a new genus, Emergomyces (Es.), which contains introduced to a host (Figures 1 and 2). As discussed
Es. pasterurianus, Es. africanus [51], and other novel above, the pathogenic phase of Emmonsia is characterized
species: Es. orientalis [62] and Es. canadensis (Figure 1) by adiaspores, spherule-like structures, while Coccidioides
[63]. Recent studies demonstrate that E. pasterurianus has endosporulating spherules unique among fungal
did not cluster with E. parva or E. crescens and with the pathogens. The processes regulating these morphological
discovery of Es. africanus, Emmonsia pasterurianus was re- switches is largely unknown.
named Emergomyces pasterurianus [51]. Infections due to
Emergomyces occur endemically in South Africa but have As discussed above, studies have found genes with similar
recently been reported in Canada, New Mexico, and function associated with dimorphism and virulence (BAD1,
Colorado (Figure 3) [53,63]. Recent studies by Jiang DRK1, CBP, and YPS3). Some factors are associated with
et al. demonstrate the morphological features of Emmonsia multiple fungal pathogens (DRK1 and BAD1; H. capsulatum
and Emergomyces in both the environment and the host. and B. dermatitidis) while others (YPS3 and CBP) have been
Emmonsia spp. are morphologically characterized by shown to be specific to Histoplasma such as YPS3, which has
adiaspores or adiaspore-like cells in the host while no sequence homology to any other gene in fungal pathogens
Emergomyces spp. are characterized by yeast cells in the [37,39,55,56]. Studies have demonstrated that a(1-3)glucan,
host environment (Figure 2) [53]. Little is known about a major polysaccharide in the fungal cell wall, is a virulence
the virulence factors in this group, and additional work is factor conserved across multiple dimorphic fungal patho-
needed to better understand how and why these gens. Focusing on the Onygenales, studies utilized RNAi to
organisms are emerging as significant pathogens. deplete a(1-3)glucan from H. capsulatum and the organism
was no longer able to kill macrophages or cause disease in
Paracoccidioides mice [72]. Additionally, studies observed decreased a(1–3)
Paracoccidioides spp. are the causative agents of paracoc- glucan content in the cell walls of attenuated strains of
cidioidomycosis, a pulmonary fungal infection endemic to Blastomyces and Paracoccidioides [73,74]. To better
Latin America, ranging from southern Mexico to northern understand the evolutionary histories of dimorphic fungal
Argentina (Figure 3) [64]. Recent phylogenetic studies pathogens, recent studies have sequenced genomes of non-
have helped to uncover novel species of Paracoccidioides pathogenic (Helicocarpus griseus and Polytolypa hystricis) and
in addition to the original species P. brasiliensis (Figure 1). pathogenic species (Blastomyces, Emmonsia, Emergomyces,
Paracoccidioides lutzii is found in mid-western Brazil and Paracoccidioides, and Coccidioides) and performed compara-
morphologically is distinct producing elongated conidial tive genomic analysis across systemic, opportunistic, and

Current Opinion in Microbiology 2019, 52:55–63 www.sciencedirect.com


Dimorphic fungi Van Dyke, Teixeira and Barker 61

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