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 toward 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, whereas 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 upregulation 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. IMPORTANCE The mold Aspergillus fumigatus reproduces by the production of airborne spores (conidia), a process termed conidiation. In immunocompromised individuals, inhaled A. fumigatus conidia can germinate and form filaments that penetrate and damage lung tissues; however, conidiation does not occur during invasive infection. In this study, we demonstrate that forced activation of conidiation in filaments of A. fumigatus can arrest their growth and impair the ability of this fungus to cause disease in both an insect and a mouse model of invasive infection. Activation of conidiation was linked to profound changes in A. fumigatus metabolism, including a shift away from the synthesis of polysaccharides required for cell wall structure and virulence in favor of carbohydrates used for energy storage and stress resistance. Collectively, these findings suggest that activation of the conidiation pathway may be a promising approach for the development of new agents to prevent or treat A. fumigatus infection.

Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence

“…5A), phenotype (macroscopic or microscopic; Fig. 5B), or virulence (17,(72)(73)(74)(75)(76)(77)(78). In addition, it was reported that 40 g/ml of Dox does not affect the transcriptional profile of S. cerevisiae (79), which contrasts with the broad effect caused by only 1 g/ml Dox on global transcription in human cells (70).…”

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“…For example, the altered in vivo lesions of A. fumigatus H-MORPH colony morphotypes indicate that host morbidity is largely the result of increased inflammatory damage [13]. Similarly, constitutive induction of the asexual development program in A. fumigatus severely attenuates pathogenesis [44].…”

Aspergillus fumigatus change Gasdermin-D-dependent pyrolysis of the lung through regulating TRL2-dependent Regulatory T cells differentiation

“…Currently, therapy for disease (such as cancer, autoimmune disease), which based immune escape mechanisms, become increasingly attractive in the biomedical eld. On entry to the host, A. fumigates triggers complex and dynamic interactions with the host [(Stewart et al 2020)]. Besides, after Aspergillus fumigatus invades the host, it can cause a series of mechanisms such as immune recognition, evading immune recognition and resisting host response.…”