A genome scale census of virulence factors in the major mould pathogen of human lungs, Aspergillus fumigatus

Infectious diseases caused by fungi are a worldwide problem causing as many deaths as malaria and tuberculosis. Azole drugs are the only orally available anti-mould agents and resistance to these drugs is increasing, possibly due to their use as agricultural fungicides. There is therefore a desperate need to develop new antifungal treatments. The major fungal pathogen in the air we breathe is called I and people affected by cancer, or requiring organ transplants, are at risk of fatal infections caused by it. We do not fully understand how A. fumigtaus survives inside the lung and urgently need more basic information about this pathogen so we can begin to design future therapies. By asking which transcription factors (TFs) control the ability of A. fumigatus to cause disease, we can achieve a global view of the regulatory network which drives infection. We have created a genome-scale collection of 401 A. fumigatus bar-coded mutants, each lacking a single TF. We will now use murine infection models with the mutant library and a state of the art DNA sequencing technology, to test the virulence of all TF mutants simultaneously. To identify the genes which are regulated by pathogenicity TFs we will use ChIP-Seq analysis and transcriptome profiling (RNA-Seq). Computational analyses of these datasets will reveal the regulatory network driving pathogenicity in A. fumigatus and lead us directly to the fungal processes we need to target with new drugs.