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Reducing Aspergillus fumigatus virulence through targeted dysregulation of the conidiation pathway

ABSTRACT: Inhalation of conidia of the opportunistic mold Aspergillus fumigatus by immunocompromised hosts can lead to invasive pulmonary disease. Inhaled conidia that escape immune defenses germinate to form filamentous hyphae that invade lung tissues. Conidiation rarely occurs during invasive infection of the human host, allowing the bulk of fungal energy to be directed towards vegetative growth. We hypothesized that forced induction of conidiation during infection can suppress A. fumigatus vegetative growth, impairing the ability of this organism to cause disease. To study the effects of conidiation pathway dysregulation on A. fumigatus virulence, a key transcriptional regulator of conidiation (brlA) was expressed under the control of a doxycycline-inducible promoter. Time- and dose-dependent brlA overexpression was observed in response to doxycycline both in vitro and in vivo. Exposure of the inducible brlA overexpression strain to low doses of doxycycline under vegetative growth conditions in vitro induced conidiation, while high doses arrested growth. Overexpression of brlA attenuated A. fumigatus virulence in both an invertebrate and mouse model of invasive aspergillosis. RNA sequencing studies and phenotypic analysis revealed that brlA-overexpression results in altered cell signaling, amino acid and carbohydrate metabolism, including a marked up-regulation of trehalose biosynthesis and a downregulation in the biosynthesis of the polysaccharide virulence factor galactosaminogalactan. This proof-of-concept study demonstrates that activation of the conidiation pathway in A. fumigatus can reduce virulence and suggests that brlA-inducing small molecules may hold promise as a new class of therapeutics for A. fumigatus infection.

ORGANISM(S): Aspergillus fumigatus

PROVIDER: GSE143601 | GEO | 2020/01/15

REPOSITORIES: GEO

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Project description:In filamentous fungi, secondary metabolism is often linked with developmental processes such as conidiation. In this study we analyzed the link between secondary metabolism and conidiation in the main industrial producer of the β-lactam antibiotic penicillin, the ascomycete Penicillium chrysogenum. Therefore, we generated mutants defective in two central regulators of conidiation, the transcription factors BrlA and StuA, respectively. Inactivation of both BrlA and StuA blocked conidiation and altered hyphal morphology during growth on solid media, as shown by light and scanning electron microscopy, but did not affect biomass production during liquid submerged growth. Genome-wide transcriptional profiling identified a complex StuA- and BrlA-dependent regulatory network, including genes previously shown to be involved in development and secondary metabolism. Remarkably, inactivation of StuA, but not BrlA, drastically down-regulated expression of the penicillin biosynthetic gene cluster during solid and liquid submerged growth. In agreement, penicillin V production was wild type-like in BrlA-deficient strains but 99 % decreased in StuA-deficient strains during liquid submerged growth as shown by HPLC analysis. Thus, among identified regulators of penicillin V production StuA has the most severe influence. Over-expression of StuA increased the transcript levels of BrlA and AbaA (another developmental regulator), de-repressed conidiation during liquid submerged growth, but did not affect penicillin V productivity. Taken together, these data demonstrate an intimate but not exclusive link between regulation of development and secondary metabolism in P. chrysogenum. Transcriptomes of PcbrlA- and PcstuA- deletion mutants were compared with expression data from recipient strain deltaPcku70 as a control Mycelia from the transformants and the reference strain were harvested at successive stages of development for RNA extraction and hybridization on Affymetrix microarrays.

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Reducing Aspergillus fumigatus virulence through targeted dysregulation of the conidiation pathway

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