Abstract
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.
Highlights
A small fraction of the estimated 1.5 million fungal species on Earth can colonise and infect human beings
While gliotoxin biosynthesis is dispensable for virulence in some murine models, our analysis demonstrates that this host environment is conducive to immunotoxin production, and further insights on virulence mechanisms relevant to neutropenia and/or corticosteroid therapy await comparative analyses of fungal gene expression in each of these strikingly different host settings, an analysis which is currently underway in our laboratory
We present a methodology for A. fumigatus transcript profiling during initiation of murine infection and a comparative analysis of global transcriptional programming, in laboratory culture and the mammalian lung
Summary
A small fraction of the estimated 1.5 million fungal species on Earth can colonise and infect human beings. The ascomycetes’ ecologically important saprophytism demands metabolic diversity and species-specific inventories of secreted enzymes. These are attributes which may contribute to the pathogenicity of certain species in plants and humans and have long influenced interpretations of virulence[1,2]. Most A. fumigatus infections are a direct consequence of the enormous propensity of A. fumigatus spores for airborne dispersal in large quantities, such that the human lung is constantly exposed to them. Its nature and severity is governed by the status of the host, which determines whether the spores are cleared effectively or whether they go on to germinate in, colonise, or even to invade the surrounding lung tissue[3]. Ex vivo and epidemiological analyses place macrophages and neutrophils on the Author Summary
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