A Ssd1 homolog impacts trehalose and chitin biosynthesis and contributes to virulence inAspergillus fumigatus

Abstract

AbstractRegulation of fungal cell wall biosynthesis is critical to maintain cell wall integrity in the face of dynamic fungal infection microenvironments. In this study, we observe that a yeastssd1homolog,ssdA,in the filamentous fungusAspergillus fumigatusis involved in trehalose and cell wall homeostasis. AnssdAnull mutant strain exhibited an increase in trehalose levels and a reduction in colony growth rate. Over-expression ofssdAin contrast perturbed trehalose biosynthesis and reduced conidia germination rates. ThessdAnull mutant strain was more resistant to cell wall perturbing agents while over-expression ofssdApromoted increased sensitivity. Over-expression ofssdAsignificantly increased chitin levels and both loss and over-expression ofssdAaltered sub-cellular localization of the class V chitin synthase CsmA. Strikingly, over-expression ofssdAabolished adherence to abiotic surfaces and severely attenuated the virulence ofA. fumigatusin a murine model of invasive pulmonary aspergillosis. In contrast, despite the severein vitrofitness defects observed upon loss ofssdA,neither surface adherence or murine survival was impacted. In conclusion,A. fumigatusSsdA plays a critical role in cell wall homeostasis that alters fungal-host interactions.ImportanceLife threatening infections caused by the filamentous fungusAspergillus fumigatusare increasing along with a rise in fungal strains resistant to contemporary antifungal therapies. The fungal cell wall and the associated carbohydrates required for its synthesis and maintenance are attractive drug targets given that many genes encoding proteins involved in cell wall biosynthesis and integrity are absent in humans. Importantly, genes and associated cell wall biosynthesis and homeostasis regulatory pathways remain to be fully defined inA. fumigatus.In this study, we identify SsdA, a model yeast Ssd1p homolog, as an important component of trehalose and fungal cell wall biosynthesis inA. fumigatusthat consequently impacts fungal virulence in animal models of infection.