117 research outputs found
Amino acid biosynthetic routes as drug targets for pulmonary fungal pathogens:what is known and why do we need to know more?
Bayesian detection of piecewise linear trends in replicated time-series with application to growth data modelling
We consider the situation where a temporal process is composed of contiguous
segments with differing slopes and replicated noise-corrupted time series
measurements are observed. The unknown mean of the data generating process is
modelled as a piecewise linear function of time with an unknown number of
change-points. We develop a Bayesian approach to infer the joint posterior
distribution of the number and position of change-points as well as the unknown
mean parameters. A-priori, the proposed model uses an overfitting number of
mean parameters but, conditionally on a set of change-points, only a subset of
them influences the likelihood. An exponentially decreasing prior distribution
on the number of change-points gives rise to a posterior distribution
concentrating on sparse representations of the underlying sequence. A
Metropolis-Hastings Markov chain Monte Carlo (MCMC) sampler is constructed for
approximating the posterior distribution. Our method is benchmarked using
simulated data and is applied to uncover differences in the dynamics of fungal
growth from imaging time course data collected from different strains. The
source code is available on CRAN.Comment: Accepted to International Journal of Biostatistic
Siderophore Biosynthesis But Not Reductive Iron Assimilation Is Essential for Aspergillus fumigatus Virulence
The ability to acquire iron in vivo is essential for most microbial pathogens. Here we show that Aspergillus fumigatus does not have specific mechanisms for the utilization of host iron sources. However, it does have functional siderophore-assisted iron mobilization and reductive iron assimilation systems, both of which are induced upon iron deprivation. Abrogation of reductive iron assimilation, by inactivation of the high affinity iron permease (FtrA), has no effect on virulence in a murine model of invasive aspergillosis. In striking contrast, A. fumigatus l-ornithine-N 5-monooxygenase (SidA), which catalyses the first committed step of hydroxamate-type siderophore biosynthesis, is absolutely essential for virulence. Thus, A. fumigatus SidA is an essential virulence attribute. Combined with the absence of a sidA ortholog—and the fungal siderophore system in general—in mammals, these data demonstrate that the siderophore biosynthetic pathway represents a promising new target for the development of antifungal therapies
The Translation of Japanese Literature in Spain
10 páginas, 3 figuras, I figura, 1 tabla -- PAGS nros. 291-300Many fungi grow over a wide pH range and their gene expression is tailored to the environmental pH. In Aspergillus nidulans, the transcription factor PacC, an activator of genes expressed in alkaline conditions and a repressor of those expressed in acidic conditions, undergoes two processing proteolyses, the first being pH-signal dependent and the second proteasomal. Signal transduction involves a 'go-between' connecting two complexes, one of which comprises two plasma membrane proteins and an arrestin and the other comprises PacC, a cysteine protease, a scaffold and endosomal components. The Saccharomyces cerevisiae PacC orthologue, Rim101p, differs in that it does not undergo the second round of proteolysis and it functions directly as a repressor only. PacC/Rim101-mediated pH regulation is crucial to fungal pathogenicityPeer reviewe
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
The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus
The frequency of antifungal resistance, particularly to the azole class of ergosterol biosynthetic inhibitors, is a growing global health problem. Survival rates for those infected with resistant isolates are exceptionally low. Beyond modification of the drug target, our understanding of the molecular basis of azole resistance in the fungal pathogen Aspergillus fumigatus is limited. We reasoned that clinically relevant antifungal resistance could derive from transcriptional rewiring, promoting drug resistance without concomitant reductions in pathogenicity. Here we report a genome-wide annotation of transcriptional regulators in A. fumigatus and construction of a library of 484 transcription factor null mutants. We identify 12 regulators that have a demonstrable role in itraconazole susceptibility and show that loss of the negative cofactor 2 complex leads to resistance, not only to the azoles but also the salvage therapeutics amphotericin B and terbinafine without significantly affecting pathogenicity
Fungal and host protein persulfidation are functionally correlated and modulate both virulence and antifungal response
From PLOS via Jisc Publications RouterHistory: received 2020-06-02, accepted 2021-04-27, collection 2021-06, epub 2021-06-01Publication status: PublishedFunder: Medical Research Council; funder-id: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/N008707/1Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research; funder-id: http://dx.doi.org/10.13039/501100000849; Grant(s): NC/P002390/1Funder: Fundação para a Ciência e a Tecnologia; funder-id: http://dx.doi.org/10.13039/501100001871; Grant(s): SFRH/BPD/96176/201Funder: Fundação para a Ciência e a Tecnologia; funder-id: http://dx.doi.org/10.13039/501100001871; Grant(s): IF/00735/2014Funder: deutsche forschungsgemeinschaft; Grant(s): CRC/TRR 124Funder: Fondation de l'Avenir pour la Recherche Médicale Appliquée; funder-id: http://dx.doi.org/10.13039/100007380Aspergillus fumigatus is a human fungal pathogen that can cause devastating pulmonary infections, termed “aspergilloses,” in individuals suffering immune imbalances or underlying lung conditions. As rapid adaptation to stress is crucial for the outcome of the host–pathogen interplay, here we investigated the role of the versatile posttranslational modification (PTM) persulfidation for both fungal virulence and antifungal host defense. We show that an A. fumigatus mutant with low persulfidation levels is more susceptible to host-mediated killing and displays reduced virulence in murine models of infection. Additionally, we found that a single nucleotide polymorphism (SNP) in the human gene encoding cystathionine γ-lyase (CTH) causes a reduction in cellular persulfidation and correlates with a predisposition of hematopoietic stem cell transplant recipients to invasive pulmonary aspergillosis (IPA), as correct levels of persulfidation are required for optimal antifungal activity of recipients’ lung resident host cells. Importantly, the levels of host persulfidation determine the levels of fungal persulfidation, ultimately reflecting a host–pathogen functional correlation and highlighting a potential new therapeutic target for the treatment of aspergillosis
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
Amino acid biosynthetic routes as drug targets for pulmonary fungal pathogens: what is known and why do we need to know more?
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
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