RESUMEN
Aspergillus fumigatus is the most common cause of invasive mold disease in humans. The mechanisms underlying the adherence of this mold to host cells and macromolecules have remained elusive. Using mutants with different adhesive properties and comparative transcriptomics, we discovered that the gene uge3, encoding a fungal epimerase, is required for adherence through mediating the synthesis of galactosaminogalactan. Galactosaminogalactan functions as the dominant adhesin of A. fumigatus and mediates adherence to plastic, fibronectin, and epithelial cells. In addition, galactosaminogalactan suppresses host inflammatory responses in vitro and in vivo, in part through masking cell wall ß-glucans from recognition by dectin-1. Finally, galactosaminogalactan is essential for full virulence in two murine models of invasive aspergillosis. Collectively these data establish a role for galactosaminogalactan as a pivotal bifunctional virulence factor in the pathogenesis of invasive aspergillosis.
Asunto(s)
Aspergilosis/inmunología , Aspergillus fumigatus/inmunología , Aspergillus fumigatus/patogenicidad , Polisacáridos Fúngicos/inmunología , Polisacáridos/inmunología , Factores de Virulencia/inmunología , beta-Glucanos/inmunología , Animales , Aspergilosis/genética , Aspergilosis/patología , Aspergillus fumigatus/genética , Carbohidrato Epimerasas/genética , Carbohidrato Epimerasas/inmunología , Línea Celular , Modelos Animales de Enfermedad , Polisacáridos Fúngicos/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/inmunología , Humanos , Hifa/genética , Hifa/inmunología , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Ratones , Polisacáridos/genética , Factores de Virulencia/genéticaRESUMEN
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 DeltatpsAB double mutant had delayed germination at 37 degrees C, suggesting a developmental defect. At 50 degrees C, the majority of DeltatpsAB spores were found to be nonviable, and those that were viable had severely delayed germination, growth, and subsequent sporulation. DeltatpsAB spores were also susceptible to oxidative stress. Surprisingly, the DeltatpsAB 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.
