New drug targets for pathogenic fungi
The cost of fungal diseases is very high both in agriculture and human health. Every year, rice blast fungus causes crop losses that would feed 60 million people and some human fungal infections, notably Candida, can be fatal for immunocompromised patients. To make major headway in the development of new antifungal drugs, the EU-funded ARIADNE(opens in new window) (Signaling circuitry controlling fungal virulence: identification and characterization of conserved and specific fungal virulence genes as common antifungal targets) project has amassed a vast amount of data on the molecular dynamics of fungal pathogenesis and signal transduction. The researchers focused on central signalling cascades that have been conserved through evolution in all fungal pathogens and play a major role in infection. ARIADNE has built a significant database containing the genome, transcriptome and proteome of key pathogenic fungi. These included notorious human pathogens Aspergillus fumigatus and Candida albicans as well as plant pathogens Fusarium oxysporum that infects a range of crops and Magnaporthe grisea that devastates rice crops. Analysis of the data sets has yielded important and significant insight into the pathogenesis of fungi. Downstream of mitogen-activated protein kinase (MAPK) pathways, vital for infection-related morphogenesis and virulence, the researchers found new target genes. The importance of MAPK signalling for chemotropic sensing of its host Fusarium has also been elucidated. Plants have their own arsenal of infection resistance pathways, but these are often breached by the fungi. A pH 5-induced resistance network to cell wall degrading enzymes (CWDEs) was identified. CWDEs allow the fungus access to the plant through the cell wall barrier. M. grisea (rice blast fungus) revealed effector proteins involved in suppression of plant immunity. Pathogenic fungi have elaborate mechanisms for infecting the host. The researchers developed a novel non-vertebrate animal infection model for F. oxysporum, a multi-host fungus for plants and a sometimes deadly human pathogen in an immunocompromised situation. Furthermore, a new tool to study the pharmacological effect of inhibitors was established with murine macrophages that have phagocytosed (ingested) F. oxysporum cells. Collaboration between institutes of excellence in fungal pathogenicity and industrial partners will help develop new treatments for fungal infection based on ARIADNE research outcomes. The project has also trained a new generation of multidisciplinary scientists who are experienced in knowledge transfer between academic and industrial sectors and have therefore adopted a science-to-business approach.
