Mechanistic basis of effector-mediated pneumocyte killing in the pathogenic mould, A. fumigatus

The common soil-dwelling mould Aspergillus fumigatus continually releases airborne spores and humans inhale several hundred of these daily. Clinical and laboratory studies have revealed that, in individuals suffering immune dysfunction, inhaled A. fumigatus spores can germinate - much like plant seeds - and form elongated structures called hyphae (singular hypha), which penetrate and damage human lung tissue and surrounding blood vessels. In addition to the physical penetration of lung tissues, invasion by A. fumigatus hyphae also involves multiple secreted factors, such as proteases and toxins, that are produced during and after the spore to hypha switch. The interactions of the A. fumigatus spore and hyphal forms with host cells is an integral feature of disease progression, the timing and underlying mechanisms of which we have precisely characterised. Recently we identified 45 fungal proteins which are required to elicit lung cell death. The aim of this project is to characterise the way in which these proteins damage human cells and how they are secreted from the invasive hypha. Beceause the proteins are important for causing death of human lungs cells, they might in future provide tools for diagnosing and/or preventing tissue invasive fungal lung disease.