Sub-Telomere Directed Gene Expression during Initiation of Invasive Aspergillosis

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.

The putative flavin carrier family FlcA-C is important forAspergillus fumigatusvirulence

“…The flcB gene (but not flcA and flcC) is more expressed in vivo during initiation of murine infection 43 ; however, we have not observed increased flcA, -B and -C mRNA accumulation induced either by human platelets in vitro or during airway epithelial cells interacting with A. fumigatus conidia. 44,45 This represents the first evidence that a FLC homolog to be involved in virulence, since the impact of the C. albicans FLC null mutants on virulence was not evaluated.…”

A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus

“…Other studies reported that transcriptional changes during the initiation of invasive aspergillosis involve more than 1,000 genes. However, in those studies, the authors compared fungal growth in vivo (during infection) vs. in vitro (on culture media) [21,22]. Therefore, the interpretation of these results and the subsequent conclusions have to be taken with caution, since transcriptomic studies depend on the experimental design, the time points studied and the type of reference sample used [28].…”

“…In addition to these findings, studies of the changes in gene expression during encounters with host tissues or in stress conditions have presented genes encoding proteins possibly involved in virulence [17–20]. However, up to date, only a few experiments have been performed using organisms isolated from bronchoalveolar lavage from intranasal infection models [21,22]. …”

When green and red mycology meet: Impressions from an interdisciplinary forum on virulence mechanisms of phyto- and human-pathogenic fungi

“…As first speaker, Elaine Bignell, deputy director of the recently established Manchester Fungal Infection Group (MFIG), provided insights into the transcriptional response of A. fumigatus under host-imposed stress. 24,25 Moreover, she highlighted the presumed role of secreted factors for epithelial damage and introduced a mechanistic model on fungal persistence in the host lung environment. 26 The contribution of alveolar epithelial cells in fungicidal defense was demonstrated by in vitro studies as well as in murine infections, thereby affecting the immunotolerant disposal of inhaled A. fumigatus conidia.…”