Role of Trehalose Biosynthesis in Aspergillus fumigatus Development, Stress Response, and Virulence

Abstract

Aspergillus fumigatus is a pathogenic mold which causes invasive, often fatal, pulmonary disease in immunocompromised individuals. Recently, proteins involved in the biosynthesis of trehalose have been linked with virulence in other pathogenic fungi. We found that the trehalose content increased during the developmental life cycle of A. fumigatus, throughout which putative trehalose synthase genes tpsA and tpsB were significantly expressed. The trehalose content of A. fumigatus hyphae also increased after heat shock but not in response to other stressors. This increase in trehalose directly correlated with an increase in expression of tpsB but not tpsA. However, deletion of both tpsA and tpsB was required to block trehalose accumulation during development and heat shock. The ⌬tpsAB double mutant had delayed germination at 37°C, suggesting a developmental defect. At 50°C, the majority of ⌬tpsAB spores were found to be nonviable, and those that were viable had severely delayed germination, growth, and subsequent sporulation. ⌬tpsAB spores were also susceptible to oxidative stress. Surprisingly, the ⌬tpsAB double mutant was hypervirulent in a murine model of invasive aspergillosis, and this increased virulence was associated with alterations in the cell wall and resistance to macrophage phagocytosis. Thus, while trehalose biosynthesis is required for a number of biological processes that both promote and inhibit virulence, in A. fumigatus the predominant effect is a reduction in pathogenicity. This finding contrasts sharply with those for other fungi, in which trehalose biosynthesis acts to enhance virulence.

Role of Aspergillus fumigatus DvrA in Host Cell Interactions and Virulence

“…EUKARYOT. CELL mutants all induced an exaggerated host inflammatory response (1,9,18). Collectively, these results suggest that the composition of the cell wall plays a key role in determining the host inflammatory response to and virulence of A. fumigatus.…”

“…The deletion of ace2, ags3, and ecm33 is associated with enhanced virulence in murine models of invasive pulmonary aspergillosis (9,18,31). Recently we reported that an A. fumigatus double mutant lacking the trehalose biosynthesis genes tpsA and tpsB also was hypervirulent in mice (1). This mutant had the reduced expression of ags3, suggesting that a reduction in cell wall ␣(1-3)glucans contributed to its hypervirulent phenotype.…”

“…Our finding that the ⌬dvrA mutant expressed ace2, ags3, and ecm33 at wild-type levels makes it unlikely that these genes contribute to the increased virulence of this strain. However, a common finding with the ⌬dvrA, ⌬ace2, ⌬ags3, ⌬ecm33, and ⌬tpsAB mutants is an alteration in the fungal cell wall (1,6,9,18,31). Furthermore, the ⌬dvrA, ⌬ace2, ⌬ags3, and ⌬tpsAB FIG.…”

Pathway of Glycine Betaine Biosynthesis in Aspergillus fumigatus

“…Acquisition of osmoprotectants is important for the survival of the conidia and for mycelial growth of filamentous fungal pathogens such as Aspergillus fumigatus in their human host (8,9). However, the mechanisms controlling the osmotic pressure changes during the biological cycle of fungal species remain insufficiently understood.…”

“…However, the mechanisms controlling the osmotic pressure changes during the biological cycle of fungal species remain insufficiently understood. Although trehalose has been repeatedly cited as the major metabolite involved in the osmoprotection of A. fumigatus, several arguments suggest that it is not the only one: (i) trehalose is rapidly degraded upon induction of conidial germination and increases again later during mycelial growth; (ii) two metabolic pathways for the biosynthesis of trehalose have been identified, but their respective roles have not been evaluated; and (iii) other polyols have been also suggested to be associated with changes in osmotic pressure (8,9). This also raised the question of the existence of other molecules that could be associated with osmoprotection during the fungal biological cycle.…”