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Abstract
Aspergillus fumigatus is a filamentous fungus that can cause a life-threatening invasive pulmonary aspergillosis (IPA) in immunocompromised individuals. We previously characterized an exo-sialidase from A. fumigatus that prefers the sialic acid substrate, 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (Kdn); hence it is a Kdnase. Sialidases are known virulence factors in other pathogens; therefore, the goal of our study was to evaluate the importance of Kdnase in A. fumigatus. A kdnase knockout strain (Δkdnase) was unable to grow on medium containing Kdn and displayed reduced growth and abnormal morphology. Δkdnase was more sensitive than wild type to hyperosmotic conditions and the antifungal agent, amphotericin B. In contrast, Δkdnase had increased resistance to nikkomycin, Congo Red and Calcofluor White indicating activation of compensatory cell wall chitin deposition. Increased cell wall thickness and chitin content in Δkdnase were confirmed by electron and immunofluorescence microscopy. In a neutropenic mouse model of invasive aspergillosis, the Δkdnase strain had attenuated virulence and a significantly lower lung fungal burden but only in animals that received liposomal amphotericin B after spore exposure. Macrophage numbers were almost twofold higher in lung sections from mice that received the Δkdnase strain, possibly related to higher survival of macrophages that internalized the Δkdnase conidia. Thus, A. fumigatus Kdnase is important for fungal cell wall integrity and virulence, and because Kdnase is not present in the host, it may represent a potential target for the development of novel antifungal agents.
Highlights
Aspergillus fumigatus is a filamentous fungus that can cause a life-threatening systemic mycosis called invasive aspergillosis (IA)
The goals of the present study were to determine whether the Aspergillus fumigatus sialidase (Kdnase) is critical for the growth and development of A. fumigatus and whether it is required for virulence
The kdnase gene on chromosome 4 was disrupted by Agrobacterium-mediated transformation of A. fumigatus using a fusion PCR construct that contained a hygromycin resistance cassette for positive selection flanked by 1000 bp kdnase up- and downstream sequences (Supplementary Figure S1)
Summary
Aspergillus fumigatus is a filamentous fungus that can cause a life-threatening systemic mycosis called invasive aspergillosis (IA). IA cases are rare in immunocompetent patients but affect those with weakened immune systems caused by immunosuppressive drug treatment, cancer or genetic polymorphisms that affect the innate immune response (Schmiedel and Zimmerli, 2016). Other less common portals of entry for invasive Aspergillus infection include the skin, gastrointestinal tract, and the eyes (Fuqua et al, 2010). IA is usually treated with the triazole antifungal, voriconazole as the primary treatment, and the polyene antibiotic, amphotericin B as an alternative. Caspofungin, an echinocandin antifungal agent, is utilized as a salvage therapy as it is generally less toxic than the other two drugs (Walsh et al, 2008; Kousha et al, 2011). The overall mortality rate for IA is approximately 50% and other factors can worsen prognosis, such as the progression of underlying malignancy, renal impairment, or recent corticosteroid treatment (Nivoix et al, 2008)
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