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bioRxiv · 10.1101/594341

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

Thammahong, A.·Dhingra, S.·Bultman, K. M.·Kerkaert, J. D.·Cramer, R. A.
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Abstract

Regulation 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 yeast ssd1 homolog, ssdA, in the filamentous fungus Aspergillus fumigatus is involved in trehalose and cell wall homeostasis. An ssdA null mutant strain exhibited an increase in trehalose levels and a reduction in colony growth rate. Over-expression of ssdA in contrast perturbed trehalose biosynthesis and reduced conidia germination rates. The ssdA null mutant strain was more resistant to cell wall perturbing agents while over-expression of ssdA promoted increased sensitivity. Over-expression of ssdA significantly increased chitin levels and both loss and over-expression of ssdA altered sub-cellular localization of the class V chitin synthase CsmA. Strikingly, over-expression of ssdA abolished adherence to abiotic surfaces and severely attenuated the virulence of A. fumigatus in a murine model of invasive pulmonary aspergillosis. In contrast, despite the severe in vitro fitness defects observed upon loss of ssdA, neither surface adherence or murine survival was impacted. In conclusion, A. fumigatus SsdA plays a critical role in cell wall homeostasis that alters fungal-host interactions.\n\nImportanceLife threatening infections caused by the filamentous fungus Aspergillus fumigatus are 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 in A. fumigatus. In this study, we identify SsdA, a model yeast Ssd1p homolog, as an important component of trehalose and fungal cell wall biosynthesis in A. fumigatus that consequently impacts fungal virulence in animal models of infection.

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Thammahong, A., Dhingra, S., Bultman, K. M., Kerkaert, J. D., Cramer, R. A.. 2019-03-31. A Ssd1 homolog impacts trehalose and chitin biosynthesis and contributes to virulence in Aspergillus fumigatus. https://doi.org/10.1101/594341

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