Effectors of tissue invasion in Aspergillus fumigatus, the major fungal pathogen of human lungs

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The often-fatal fungal lung disease invasive aspergillosis (IA) has claimed more than 8 million human lives since its emergence ~ 40 years ago. IA-related mortality is unacceptably high (50- 90%) and usually results from respiratory failure due to haemorrhage occurring at sites of fungal invasion. Given the life-saving potential of anti-invasion therapies, a high premium has been placed upon identifying effectors of tissue invasion, against which drugs and vaccines might be engineered. However, the quest for causal associations between tissue-invasive phenotypes and secreted fungal products has repeatedly failed, presumably due to likely functional redundancy amongst the effector repertoire and insufficiency of genetic approaches in A. fumigatus with which to drive high throughput analyses of secreted fungal products. Using mouse models of IA, in vitro infections of cultured human lung cells, functional genomics and a high throughput A. fumigatus gene deletion methodology we have discovered a first-in-field cohort of 42 effectors of tissue invasion (eTINs) which govern lytic death of human lung cells. We will now combine state-of-the-art genetic, single cell imaging and effector-trap approaches with our established methodological workflow to conclusively define the invasive A. fumigatus secretome and to characterise the modes of entry and/or lytic activity of the individual effectors. This work will reveal for the first time the molecular basis of tissue invasive IA pathologies and define the genomic cohort of targets against which anti-invasion therapies and novel vaccines and diagnostics can be designed.