Fungal infections are killing 1.5 million people each year, and the mould *Aspergillus fumigatus* is a prime culprit, invading lung tissue and corneas while shrugging off standard drugs. This project aims to crack the genetic code the fungus uses to punch through human tissue barriers. Current treatments are failing against rising drug resistance. The researchers have already identified a handful of protein kinases and a cell-wall maintenance pathway that appear critical for invasion. Now they will systematically knock out every gene in the fungus to find all the others involved, then test the most promising targets in living tissue and animal models. Collaborators will screen chemical libraries for compounds that block those targets. If successful, this work could reveal entirely new classes of antifungal drugs, targeting the invasion machinery itself rather than just killing the fungus. That would give clinicians a second line of defence against infections that currently have few treatment options. The project is fundamental science—understanding how a pathogen breaks into our cells—but it directly addresses a growing public health crisis where the bugs are outpacing the pharmacy.
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Fungal diseases afflict approximately 1.7 billion individuals globally, with invasive infections causing an alarming 1.5 million deaths annually. Aspergillus fumigatus, a prominent pathogen, poses a significant health threat, particularly through severe lung diseases and invasive corneal infections. The emergence of drug-resistant strains further complicates treatment, necessitating urgent therapeutic innovations. Our research proposal focuses on elucidating the genetic mechanisms underpinning A. fumigatus' tissue invasion, a crucial aspect of its pathogenicity. Leveraging advanced genetic tools and innovative in vitro barrier models, we aim to identify key genetic factors and signalling pathways governing fungal penetration. Preliminary investigations have highlighted the role of certain protein kinases and the cell wall integrity pathway in barrier penetration, shedding light on novel targets for intervention. Building on these findings, our project entails comprehensive genome-wide functional genomic profiling to uncover additional genetic determinants of tissue invasion. Subsequently, validated targets will undergo rigorous assessment in both ex vivo and in vivo models to confirm their relevance in disease progression. Furthermore, through collaborative efforts, we aim to identify potential inhibitors for validated targets, leveraging structural insights and chemical screening approaches. By unravelling the genetic blueprint driving A. fumigatus' tissue invasion, our multidisciplinary research endeavours pave the way for the development of urgently needed antifungal interventions. Through a systematic approach encompassing genetic profiling, validation studies, and inhibitor discovery, we aim to advance our understanding of fungal pathogenesis and contribute to the development of targeted therapies to combat invasive fungal infections.
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