Back to the future for dermatophyte genomics.
ABSTRACT 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.
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ABSTRACT: Dermatophytes belonging to the Trichophyton and Arthroderma genera cause skin infections in humans and animals. From genome sequencing data, we mined a conserved gene cluster among dermatophytes that are homologous to one that produces an immunosuppressive polyketide in Aspergillus fumigatus. Using a recombination-based cloning strategy in yeast, we constructed fungal heterologous expression vectors that encode the cryptic clusters. When integrated into the model Aspergillus nidulans host, a structurally related compound neosartoricin B was formed, suggesting a possible role of this compound in the pathogenesis of these strains.ACS Synthetic Biology 06/2013; · 3.95 Impact Factor
Back to the Future for Dermatophyte Genomics
Zeyana S. Rivera, Liliana Losada, and William C. Nierman
J. Craig Venter Institute, Rockville, Maryland, USA
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
gillusgenomicssincetheinitialpublicationofthefirstthree Aspergillus genomesequencesin2005,aneventthatstimulatedim-
portantstudiesofthepathogenic Aspergillus species.Fromthese7yearsof Aspergillus history,weoffersomespeculationonthe
genome sequencing and analysis of five additional dermato-
mentary, we will situate this report in the context of current der-
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-
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-
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
.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-
nez et al. (1) report that the sequenced dermatophytes are enriched
contribute to their ability to cause disease, an observation that mir-
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
recent paper by Martinez et al. in this journal reported the
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
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-
and secreted enzymes involved in secondary metabolite produc-
tion. The genome sequences of Aspergillus fumigatus, Aspergil-
Nature papers in 2005 (2–4). Shortly after that publication event,
patients, an ability that positions them as the more important
saprophytes whose niche is decaying plant material. A. oryzae,
ancestral A. flavus, has experienced centuries of human cultiva-
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, firstname.lastname@example.org.
November/December 2012 Volume 3 Issue 6 e00381-12
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
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
Sexual reproduction has been suggested as a means to revamp
the virulence of fungi via meiotic recombination, which increases
may be associated with antifungal resistance or the rate of patho-
genicity of dermatophytes (21). Like the story of sex in A. fumiga-
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
and T. tonsurans) with comparable virulence were reported using
bioinformatic tools (23). Furthermore, successful mating of T.
benefits of sex, including cross-species sexual recombination and
expansion (24). In the Aspergillus species, the APN2 and SLA2
genes, encoding a DNA lyase and cytoskeleton protein, flank the
phytes allows further studies in the pathogenesis to be explored.
The role of LysM proteins was noted for protecting dermato-
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
Discovery of the abundance of secondary-metabolite biosyn-
thetic clusters in the Aspergillus genomes has led to the identifica-
of them in virulence. A similar abundance of these clusters has
For example, melanin, which is an important virulence determi-
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-
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.
mbio.asm.orgNovember/December 2012 Volume 3 Issue 6 e00381-12
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
canis (10, 37, 38), but these have been limited in number and
coupled to genome sequences, these and other “omics” methods,
such as metabolomics, glycomics, and lipidomics, will be more
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
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.
developed around this model prior to the genome sequence pub-
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-
to all the exciting and significant findings yet to come.
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