Abstract
Regulation of fungal cell wall biosynthesis is critical to maintain cell wall integrity in dynamic fungal infection microenvironments. Genes involved in this response that impact fungal fitness and host immune responses remain to be fully defined. In this study, we observed 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 fungal colony growth rate. In contrast, overexpression of ssdA perturbed trehalose biosynthesis and reduced germination of conidia. The ssdA null mutant strain was more resistant to cell wall-perturbing agents, while overexpression of ssdA increased sensitivity. Overexpression of ssdA significantly increased chitin levels, and both loss and overexpression of ssdA altered subcellular localization of the class V chitin synthase CsmA. Strikingly, overexpression of ssdA abolished adherence to abiotic surfaces and severely attenuated the virulence of A. fumigatus in a murine model of invasive pulmonary aspergillosis. Despite the severe in vitro fitness defects observed upon loss of ssdA, neither surface adherence nor murine survival was impacted. In conclusion, A. fumigatus SsdA plays a critical role in cell wall homeostasis impacting A. fumigatus-host interactions.IMPORTANCE The incidence of life-threatening infections caused by the filamentous fungus Aspergillus fumigatus is increasing along with an increase in the number of 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 report, we identify SsdA as an important component of trehalose and fungal cell wall biosynthesis in A. fumigatus that consequently impacts the host immune response and fungal virulence in animal models of infection.
Highlights
Regulation of fungal cell wall biosynthesis is critical to maintain cell wall integrity in dynamic fungal infection microenvironments
Results of reciprocal BLASTP analyses performed with Ssd1p against the A. fumigatus genome suggested that AFUB_010850 is likely an Ssd1p ortholog and we named AFUB_010850 “ssdA.” Given the previously identified roles of TslA in trehalose and cell wall homeostasis in A. fumigatus and the known roles of ssd1 homologs in fungal cell wall biosynthesis, we hypothesized that SsdA is an important mediator of trehalose production and cell wall homeostasis in A. fumigatus
The cell wall of Aspergillus fumigatus consists of polysaccharides, including chitin
Summary
Regulation of fungal cell wall biosynthesis is critical to maintain cell wall integrity in dynamic fungal infection microenvironments Genes involved in this response that impact fungal fitness and host immune responses remain to be fully defined. We observed that a yeast ssd homolog, ssdA, in the filamentous fungus Aspergillus fumigatus is involved in trehalose and cell wall homeostasis. We identify SsdA as an important component of trehalose and fungal cell wall biosynthesis in A. fumigatus that impacts the host immune response and fungal virulence in animal models of infection. A regulatory subunit of the trehalose biosynthesis pathway, TslA, is critical for trehalose production and cell wall homeostasis in part through regulation of a class V chitin synthase enzyme, ChsE/CsmA [41]. Pulldown assays performed with TslA as bait identified a physical interaction between TslA and CsmA as well as a putative Saccharomyces cerevisiae Ssd homolog, called SsdA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
