53 research outputs found
The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. Raw data have been deposited in the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE54810. Funding: This work was supported in part by grants to EMB from the MRC (G0501164) and BBSRC (BB/G009619/1), to EMB and NDR from the Wellcome Trust (WT093596MA), to MB from Imperial College London (Division of Investigative Sciences PhD Studentship), to HH from the ERA-NET PathoGenoMics project TRANSPAT, Austrian Science Foundation (FWF I282-B09), to SGF from the National Institutes of Health, USA (R01AI073829). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD
Sub-Telomere Directed Gene Expression during Initiation of Invasive Aspergillosis
Aspergillus fumigatus is a common mould whose spores are a
component of the normal airborne flora. Immune dysfunction permits developmental
growth of inhaled spores in the human lung causing aspergillosis, a significant
threat to human health in the form of allergic, and life-threatening invasive
infections. The success of A. fumigatus as a pathogen is unique
among close phylogenetic relatives and is poorly characterised at the molecular
level. Recent genome sequencing of several Aspergillus species
provides an exceptional opportunity to analyse fungal virulence attributes
within a genomic and evolutionary context. To identify genes preferentially
expressed during adaptation to the mammalian host niche, we generated multiple
gene expression profiles from minute samplings of A. fumigatus
germlings during initiation of murine infection. They reveal a highly
co-ordinated A. fumigatus gene expression programme, governing
metabolic and physiological adaptation, which allows the organism to prosper
within the mammalian niche. As functions of phylogenetic conservation and
genetic locus, 28% and 30%, respectively, of the
A. fumigatus subtelomeric and lineage-specific gene
repertoires are induced relative to laboratory culture, and physically clustered
genes including loci directing pseurotin, gliotoxin and siderophore biosyntheses
are a prominent feature. Locationally biased A. fumigatus gene
expression is not prompted by in vitro iron limitation, acid,
alkaline, anaerobic or oxidative stress. However, subtelomeric gene expression
is favoured following ex vivo neutrophil exposure and in
comparative analyses of richly and poorly nourished laboratory cultured
germlings. We found remarkable concordance between the A.
fumigatus host-adaptation transcriptome and those resulting from
in vitro iron depletion, alkaline shift, nitrogen
starvation and loss of the methyltransferase LaeA. This first transcriptional
snapshot of a fungal genome during initiation of mammalian infection provides
the global perspective required to direct much-needed diagnostic and therapeutic
strategies and reveals genome organisation and subtelomeric diversity as
potential driving forces in the evolution of pathogenicity in the genus
Aspergillus
Characterizing the cancer genome in lung adenocarcinoma
Somatic alterations in cellular DNA underlie almost all human cancers(1). The prospect of targeted therapies(2) and the development of high-resolution, genome-wide approaches(3-8) are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours ( n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in similar to 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 ( NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62944/1/nature06358.pd
Conservation in Aspergillus fumigatus of pH-signaling seven transmembrane domain and arrestin proteins, and implications for drug discovery
Sensory perception in fungal pathogens: Applications of the split-ubiquitin Membrane Yeast Two-Hybrid (MYTH) technique
Complete nucleotide sequences of four dsRNAs associated with a new chrysovirus infecting Aspergillus fumigatus
(c) 2010 Elsevier B.V. All rights reserved.A new double-stranded RNA (dsRNA) virus designated A. fumigatus chrysovirus (AfuCV), belonging to the family Chrysoviridae, has been identified in the filamentous fungus Aspergillus fumigatus. The virus was detected in five of 390 A. fumigatus isolates screened. Analysis of purified dsRNA revealed four distinct species 3560, 3159, 3006 and 2863 base pairs in length (dsRNAs 1-4) which were cloned and sequenced. Each dsRNA contains a single open reading frame (ORF) with short 5' and 3' untranslated regions containing strictly conserved termini. The deduced 1114 amino acid (aa) protein (molecular mass=128 kDa) encoded by the dsRNA1 ORF showed homology to the RNA-dependent RNA polymerase (RdRP) of viruses belonging to the Chrysoviridae. Eight motifs characteristic of RdRPs were identified. The dsRNA2 ORF encodes the putative coat protein subunit (953aa; molecular mass=107 kDa). The dsRNA3 and dsRNA4 ORFs respectively encode putative proteins (891aa, molecular mass=99 kDa) and (847aa, molecular mass=95 kDa), both of which have significant similarity to proteins encoded by comparable chrysovirus dsRNAs. The dsRNA profile, amino acid sequence alignments, and phylogenetic analyses all indicate that AfuCV is a new species within the family Chrysoviridae.Peer reviewe
A Regulator of Aspergillus fumigatus Extracellular Proteolytic Activity Is Dispensable for Virulence▿
Virulence of the fungal pathogen Aspergillus fumigatus is in part based on the saprophytic lifestyle that this mold has evolved. A crucial function for saprophytism resides in secreted proteases that allow assimilation of proteinaceous substrates. The impact of extracellular proteolytic activities on the pathogenesis of aspergillosis, however, remains controversial. In order to address this issue, characterization of a conserved regulatory factor, PrtT, that acts on expression of secreted proteases was pursued. Expression of PrtT appears to be regulated posttranscriptionally, and the existence of an mRNA leader sequence implies translational control via eIF2α kinase signaling. Phenotypic classification of a prtTΔ deletion mutant revealed that expression of several major extracellular proteases is PrtT dependent, resulting in the inability to utilize protein as a nutritional source. Certain genes encoding secreted proteases are not regulated by PrtT. Most strikingly, the deletant strain is not attenuated in virulence when tested in a leukopenic mouse model, which makes a strong case for reconsidering any impact of secreted proteases in pulmonary aspergillosis
Oligopeptide transport and regulation of extracellular proteolysis are required for growth of Aspergillus fumigatus on complex substrates but not for virulence
The Aspergillus fumigatus transcriptional activator CpcA contributes significantly to the virulence of this fungal pathogen
Basal expression of the Aspergillus fumigatus transcriptional activator CpcA is sufficient to support pulmonary aspergillosis
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