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Steven Braem

Friday 11 September 2015

The role of opsonins in Aspergillus fumigatus host defense

Promotor: Prof. dr. J.A.G. van Strijp
Defence: 11 September 2015

The role of opsonins in Aspergillus fumigatus host defense
Aspergillus fumigatus is an important fungal pathogen and a common cause of invasive fungal infections in humans. Susceptible individuals become infected via the inhalation of dormant conidia. If the immune system fails to clear these conidia, they will swell, germinate and grow into large hyphal structures. Especially immunocompromised patients are at risk for invasive aspergillosis.

The innate immune system plays a crucial role in the combat against A. fumigatus. Neutrophils are the key effector cells and are essential in the clearance of A. fumigatus. In general, for efficient clearance by neutrophils, pathogens need to be opsonized by humoral factors to establish effective phagocytosis and intracellular killing. In this thesis, we studied the importance of opsonins in the immunity against A. fumigatus. We showed that opsonisation of A. fumigatus is mediated by the antibody-dependent classical complement pathway. Activation of the complement system results in a massive labeling of C3b on the surface of A. fumigatus and induces phagocytosis and killing by neutrophils. Healthy individuals have antibodies that recognize epitopes on the surface of A. fumigatus. Moreover, donor sera with high opsonic antibody levels correlate to efficient complement-mediated opsonisation, effective phagocytosis and killing. Low antibody levels in sera from patients with hematological malignancies are related to an increased risk for invasive aspergillosis within 40 days after neutropenia. In conclusion, the opsonization with antibodies and subsequent complement activation are important in the immunity against A. fumigatus.

In this thesis, we also identified a cell wall protein of A. fumigatus that binds surfactant protein A, an opsonin in the lung. We hypothesize that this cell wall protein functions as a ligand of surfactant protein A or as an immune evasion molecule. However, the exact function and mechanism of action of the cell wall protein needs further investigations. Finally, we studied the effect of glucocorticoids on the growth and function of A. fumigatus. Methylprednisolone and hydrocortisone exposure induces growth of A. fumigatus, while dexamethasone does not alter growth. The effect of methylprednisolone on the adaptation of A. fumigatus was examined by gene expression profiling. Methylprednisolone exposure induces the expression of hydrophobin genes and alteres the expression of genes involved in melanin biosynthesis and gliotoxin biosynthesis. These responses of A. fumigatus on glucocorticoid exposure possibly influence its virulence.

The findings described in this thesis contribute to a better understanding of the pathogenicity of A. fumigatus, its interactions with the host, and the knowledge needed to develop novel treatment strategies.