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Back to the Future for Dermatophyte Genomics

Article · Literature Review · October 2012with14 Reads
DOI: 10.1128/mBio.00381-12 · Source: PubMed
Abstract
Dermatophytes are a uniquely pathogenic group of fungi that cause most common fungal infections globally. The major cause of athlete’s foot is Trichophyton rubrum, a pathogen of human skin. A recent paper in this journal reported the sequencing and analysis of five additional genome sequences, including that of Trichophyton rubrum. These five join the existing two additional genome sequences to bring the total to seven dermatophyte genome sequences, a notable milestone in the study of these fungi. These additional genomes set the stage for future genome-supported studies on the biology, pathogenicity, and host specificity of this important group of pathogens. To predict how this future might play out, we review the history of Aspergillus genomics since the initial publication of the first three Aspergillus genome sequences in 2005, an event that stimulated important studies of the pathogenic Aspergillus species. From these 7 years of Aspergillus history, we offer some speculation on the future of dermatophyte studies supported by the genome sequences given the similarities, differences, and relative levels of support for studies in these two groups of fungi and the diseases they cause.
Back to the Future for Dermatophyte Genomics
Zeyana S. Rivera, Liliana Losada, and William C. Nierman
J. Craig Venter Institute, Rockville, Maryland, USA
ABSTRACT Dermatophytes are a uniquely pathogenic group of fungi that cause most common fungal infections globally. The
major cause of athlete’s foot is Trichophyton rubrum, a pathogen of human skin. A recent paper in this journal reported the se-
quencing and analysis of five additional genome sequences, including that of Trichophyton rubrum. These five join the existing
two additional genome sequences to bring the total to seven dermatophyte genome sequences, a notable milestone in the study
of these fungi. These additional genomes set the stage for future genome-supported studies on the biology, pathogenicity, and
host specificity of this important group of pathogens. To predict how this future might play out, we review the history of Asper-
gillus genomics since the initial publication of the first three Aspergillus genome sequences in 2005, an event that stimulated im-
portant studies of the pathogenic Aspergillus species. From these 7 years of Aspergillus history, we offer some speculation on the
future of dermatophyte studies supported by the genome sequences given the similarities, differences, and relative levels of sup-
port for studies in these two groups of fungi and the diseases they cause.
A
recent paper by Martinez et al. in this journal reported the
genome sequencing and analysis of five additional dermato-
phyte species, bringing the total number to seven (1). In this com-
mentary, we will situate this report in the context of current der-
matophyte genomics and speculate on the future of the field based
on the advances made in Aspergillus genomics after the first three
Aspergillus genomes were sequenced in 2005 (2–4).
Dermatophytes are a uniquely pathogenic group of fungi that
cause most common fungal infections globally (5). Dermato-
phytic fungi are contained within three genera, Trichophyton, Epi-
dermophyton, and Microsporum. In the United States alone, mil-
lions of individuals seek treatment for dermatophyte infections
annually, translating into an economic burden estimated at
$400 million per year (6). Moreover, large-scale epidemics have
been reported in American troops in conflicts in Europe and an
urban childcare center outbreak (7, 8). The knowledge surround-
ing the mode by which these pathogens cause disease is insuffi-
cient, perhaps due to lack of research utilizing modern molecular
tools. Due to this deficiency, the development of effective thera-
peutics has been stunted. Genetic tools have been underutilized in
the characterization of these fungi, resulting in a lack of sequenced
dermatophyte genomes and their pathogenicity (9).
As noted, seven whole-genome sequences of dermatophyte
species have now been generated (see the Broad Institute’s Der-
matophyte Comparative Database at http://www.broadinstitute.org
/annotation/genome/dermatophyte-comparative/MultiHome
.html): the nuclear genome and mitochondrial sequences of Mi-
crosporum canis, Microsporum gypseum, Trichophyton equinum,
Trichophyton rubrum, and Trichophyton tonsurans (1), as well as
the availability of Arthroderma benhamiae and Trichophyton ver-
rucosum genome sequences (10). In their comparative study, Marti-
nez et al. (1) report that the sequenced dermatophytes are enriched
relative to other human-associated fungi with four gene families that
contribute to their ability to cause disease, an observation that mir-
rors the original analysis of the first two dermatophyte genomes (10).
These include (i) proteases, secreted to degrade skin, that reportedly
act as virulence factors; (ii) kinases, including pseudokinases, that are
involved in signaling necessary for adapting to the skin niche; (iii)
secondary metabolites, compounds that act as toxins, immune sys-
tem modulators, or signals in the interactions between fungus and
host; and (iv) a class of proteins (LysM) that appear to bind and mask
cell wall components and carbohydrates, thus avoiding the host’s im-
mune response to the fungi. Overall, these genome sequence identi-
fications are important for revealing genome components that have
the potential to further our understanding of the pathogenicity of
dermatophytes. The availability of these sequence and analysis data
will provide researchers large amounts of useful information that will
provide power to studies aimed to decipher and interpret the molec-
ular basis of host colonization, invasion, and specialization.
The observations about the dermatophyte genomes are remi-
niscent of the observations made on the first three Aspergillus ge-
nomes that were sequenced and analyzed. This is not surprising
given that all dermatophytes and Aspergilli belong to the same
phylum, Ascomycota. Characterization and analysis of many
virulence-associated traits in Aspergillus species (1) may be useful
in the search for such traits in dermatophyte genomes. Addition-
ally, Aspergillus pathogens have been the subject of medically im-
portant research, targeting genes associated with replication cycles
and secreted enzymes involved in secondary metabolite produc-
tion. The genome sequences of Aspergillus fumigatus, Aspergil-
lus nidulans, and Aspergillus oryzae were reported in back-to-back
Nature papers in 2005 (2– 4). Shortly after that publication event,
the sequence of Aspergillus flavus was completed (11). A. fumigatus
and A. flavus cause invasive aspergillosis in immunocompromised
patients, an ability that positions them as the more important
fungal pathogens in this group. A. flavus is also an important crop
plant pathogen. All of these fungi but A. oryzae are environmental
saprophytes whose niche is decaying plant material. A. oryzae,
whose genome sequence revealed it to be essentially a derivative of
ancestral A. flavus, has experienced centuries of human cultiva-
tion as a key ingredient in the production of sake, miso, soy sauce,
and other Japanese foods. At the time of the genome sequence
Published 30 October 2012
Citation Rivera ZS, Losada L, Nierman WC. 2012. Back to the future for dermatophyte
genomics. mBio 3(6):e00381-12. doi:10.1128/mBio.00381-12.
Copyright © 2012 Rivera et al. This is an open-access article distributed under the terms
of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License,
which permits unrestricted noncommercial use, distribution, and reproduction in any
medium, provided the original author and source are credited.
Address correspondence to William C. Nierman, wnierman@jcvi.org.
COMMENTARY
November/December 2012 Volume 3 Issue 6 e00381-12
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mbio.asm.org 1
publications, all but A. nidulans were presumed to be asexual. As
was the case for dermatophytes, the genome analysis of these
aspergilli revealed several striking features, including a surprising
abundance of secondary metabolite biosynthetic gene clusters, a
full set of sexual cycle genes even in the presumed asexual strains,
and an abundance of secreted degradative enzymes. The Aspergil-
lus genomes inspired a burst of studies that leveraged these ge-
nome sequences, as overviewed in Fig. 1 (12–20). Subsequent
post-genome sequence studies have revealed the identity of nu-
merous products of the secondary-metabolite biosynthetic clus-
ters and the roles of some of them in A. fumigatus and A. flavus
virulence; have identified conditions for in vitro sexual cycles in A.
fumigatus and A. flavus, which has led to genetic analysis studies of
these organisms that are now under way; and have supported
studies of the roles of many of the secreted proteases and other
degradative enzymes in virulence. In addition, multiple strains of
A. fumigatus and A. flavus have been sequenced, with the total of
A. fumigatus sequences completed or under way approaching 100
(http://gsc.jcvi.org/projects/gsc/a_fumigatus/index.php).
Sexual reproduction has been suggested as a means to revamp
the virulence of fungi via meiotic recombination, which increases
the population diversity, and via mating on the human host. These
may be associated with antifungal resistance or the rate of patho-
genicity of dermatophytes (21). Like the story of sex in A. fumiga-
tus, some dermatophytes, which were once assumed to be asexual,
have been demonstrated to possess sexual cycles as well (22).
Based on these studies, prediction of unexposed sexual cycles can
be assumed from the dermatophytes containing functional sex
genes. Recently, identification of the mating type locus (MAT) of
five dermatophytes (M. canis, M. gypseum, T. equinum, T. rubrum,
and T. tonsurans) with comparable virulence were reported using
bioinformatic tools (23). Furthermore, successful mating of T.
rubrum with Arthroderma simii suggests that these species have the
benefits of sex, including cross-species sexual recombination and
adaptation, that may outweigh the efficiencies of an asexual clonal
expansion (24). In the Aspergillus species, the APN2 and SLA2
genes, encoding a DNA lyase and cytoskeleton protein, flank the
MAT loci (25). However, those MAT genes for dermatophytes are
essentially identical and linked on one side of the MAT locus (23).
The discovery and characterization of the MAT locus of dermato-
phytes allows further studies in the pathogenesis to be explored.
The role of LysM proteins was noted for protecting dermato-
phytes from host immune detection. The importance of these pro-
teins in avoiding detection by the host immune system is sup-
ported by the observation that during dermatophyte infection,
defective or absent cell-mediated immunity predisposes the host
to chronic or recurrent dermatophyte infection (26). Previously,
expression of hydrophobin has been demonstrated to inhibit im-
mune recognition in A. fumigatus (27). Dermatophytes A. benha-
miae and T. verrucosum, both shown to activate human inflam-
matory infections, also display moderate expression of a surface
hydrophobin gene, suggesting a possible role in immune response
functions (10).
Discovery of the abundance of secondary-metabolite biosyn-
thetic clusters in the Aspergillus genomes has led to the identifica-
tion of the products of many of these clusters and the roles of some
of them in virulence. A similar abundance of these clusters has
now been noted in the reported dermatophyte genome sequences.
For example, melanin, which is an important virulence determi-
nant in Aspergillus (28), was also isolated from dermatophytes (M.
canis, M. gypseum, T. equinum, T. rubrum, and T. tonsurans) in
vitro and during infection, suggesting a similar role in Aspergillus
and dermatophyte pathogenesis (29). Moreover, T. rubrum pro-
duces xanthomegnin, a toxin produced by Aspergillus in culture
and in the human host (30). Transcriptome analysis revealed dif-
ferential expression of secondary-metabolite genes during der-
matophyte and Aspergillus infections, underscoring their impor-
tance in the colonization of tissues and potentially in the
manipulation of the host inflammatory response (30). Future
studies will undoubtedly leverage the genome sequences of these
clusters in dermatophytes to identify their secondary-metabolite
products and their potential specific roles in virulence.
Given the recent major progress in the development of broad-
scale transcriptional and genome sequence-dependent analyses of
dermatophytes (10, 30–32) and a selection of functionally charac-
terized genes (33, 34), full genome sequences will fulfill a critical
urgency in the need to develop molecular genetic techniques to
study these pathogens. Molecular studies of dermatophyte
genomics and pathogenicity have been undertaken in spite of the
limited number of sequenced genomes. For example, Vermout
and colleagues used RNA silencing as a potential functional
genomics tool in M. canis to identify two proteases, SUB3 and
FIG 1 Aspergillus genomics timeline. The timeline highlights some of the numerous critical studies since the publication of the first three Aspergillus genome
sequences in 2005. The cited papers should be taken as representative, as no rigorous prioritization was imposed in selecting papers to highlight in the timeline.
Commentary
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DPPIV, coding for subtilisin and dipeptidyl peptidase, respec-
tively (35). Previous studies have also demonstrated the associa-
tion of increased keratinase with increased disease symptoms in
M. canis (36). Several studies have used proteomics to characterize
secreted and conidial proteins in T. rubrum, A. benhamiae, and M.
canis (10, 37, 38), but these have been limited in number and
applicability by the lack of genome sequence. Now that they can be
coupled to genome sequences, these and other “omics” methods,
such as metabolomics, glycomics, and lipidomics, will be more
powerful, and accordingly, will strengthen the understanding and
characterization of dermatophyte pathogenesis.
It is clear that the availability of additional dermatophyte ge-
nomes will accelerate and enhance molecular studies of these
pathogenic fungi. It is therefore most appropriate to celebrate the
publication of these new dermatophyte genomes and to note this
event as a consequential milestone in the efforts to manage the
terrible diseases caused by this group of fungi. The aspergilli and
the dermatophytes are closely related, and the new dermatophyte
genome sequences reveal features similar to those in the aspergilli.
This observation suggests commonality in how these fungi survive
and thrive in a mammalian host. Specific features of the dermato-
phytes and aspergilli diseases—such as invasiveness, fatality, and
organ involvement— have resulted in research communities with
disproportionate funding support that favored more rapid ad-
vancement in the aspergilli than in dermatophytes. Another im-
portant factor that favored the aspergilli was the strength of A.
nidulans as a model organism and the mature community that had
developed around this model prior to the genome sequence pub-
lications. However, studies of these two groups of fungi have been,
and will continue to be, synergistic, with each community taking
lessons from the other. We project that the rate of progress in
dermatophyte genomic research will accelerate now in much the
same way Aspergillus research accelerated following the publica-
tion of the Aspergillus genomes in 2005 and 2006. We look forward
to all the exciting and significant findings yet to come.
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