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A state-of-the-art effector trap to identify secreted effectors of tissue invasion in the major fungal pathogen of human lungs


Project Description

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 fungal gene products has repeatedly failed, presumably due to functional redundancy amongst the effector repertoire and a paucity of genetic approaches in A. fumigatus for high through put analyses. 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 SignalP-containing, secreted or potentially cell-surface associated, effectors of tissue invasion (eTINs) which govern cytotoxicity in 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.

Entry Requirements
The applicants are expected to have (or expect to obtain) an upper second class honours degree in a related subject area.If applicants have (or expect to obtain) a research based MSc degree, a merit or distinction level is required.

Funding Notes

This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).



As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Bertuzzi M, Hayes G, Icheoku U, Osherov N, Bignell E (2018) Anti-Aspergillus activities of the respiratory epithelium in health and disease Journal of Fungi In Press
2. Loss O, Bertuzzi M, Yu Y, Fedorova N, McCann B, Armstrong-James D, Espeso E, Read N, Nierman W, Bignell E (2017) Mutual independence of alkaline- and calcium-mediated signalling in Aspergillus fumigatus refutes the existence of a conserved druggable signalling nexus Molecular Microbiology 106:861-875
3. Johns A, Scharf DH, Gsaller F, Schmidt H, Heinekamp T, Straßburger M, Oliver JD, Birch M, Beckmann N, Dobb KS, Gilsenan J, Rash B, Bignell E, Brakhage AA, Bromley MJ. 2017. A nonredundant phosphopantetheinyl transferase, PptA, is a novel antifungal target that directs secondary metabolite, siderophore, and lysine biosynthesis in Aspergillus fumigatus and is critical for pathogenicity mBio 8:e01504-16
4. Bignell, E., Cairns, T. C., Throckmorton, K., Nierman, W. C. & Keller, N. P. (2016) Secondary metabolite arsenal of an opportunistic pathogenic fungus Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 371:1709 [IF 6.9]
5. Amich Elias, J., & Bignell, E. (2016). Amino acid biosynthetic routes as drug targets for pulmonary fungal pathogens: what is known and why do we need to know more? Current Opinion in Microbiology, 32, 151-158. [IF 6.9]

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