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Use of novel technologies for reasoned identification of antifungal drug targets: sulphur metabolism in Aspergillus fumigatus.


Project Description

Fungal diseases kill more than 1.5 million and affect over a billion people worldwide. Azoles are the only orally available antifungals and resistance to these drugs is increasing, which translates into a rise in mortality. There is therefore a desperate need to develop new treatments. Aspergillus fumigatus is the major fungal pathogen in the air we breathe and people with any kind of immune imbalance are at risk of fatal infections caused by it. Being an environmental saprophytic mould, its success in invading susceptible hosts heavily relies on its metabolic and nutritional versatility. Indeed, we have shown that interfering with sulphur metabolism, at both transcriptional and specific-pathway levels, impacts A. fumigatus pathogenicity.

In this project we aim to decipher the complete fungal sulphur-related metabolic status during infection of the mammalian lung, and exploit this knowledge to identify essential traits of fungal virulence that serve as targets for novel drug development. We have already optimised the use of the state-of-the-art NanoString transcriptomic technology to assess expression of fungal genes during infection. We will use this cutting-edge in vivo transcriptomics to evaluate the dynamics of gene expression during the establishment and progression of infection. The involvement of identified relevant genes in human disease will be verified by assessing its expression in clinical samples. The role of selected gene products in fungal virulence will be scrutinized using a combination of genetic and proteomic tools, cell culture techniques and animal models. Furthermore, we have recently optimised a genetic model that allows targeting candidate genes to mimic actual treatment of established infections; employing this model we will evaluate the suitability of the identified gene products as antifungal drug targets.

This project will unravel the sulphur-related virulence traits of fungal pathogenicity and provide novel molecular targets for the development of new antifungals, a paramount clinical need.

Training/techniques to be provided -
This project will provide a multidisciplinary training involving exposure to innovative approaches to the genetic, pathological and biotechnological basis of novel drug discovery. A successful candidate will acquire a robust grounding in genetic and metabolic manipulation of pathogenic fungi and cell culture techniques. The student will receive a strong training in molecular biology techniques, particularly nucleic acid and protein isolation and manipulation. Furthermore, the student will learn state-of-the-art transcriptomic approaches and animal models of infection.

Funding Notes

Candidates are expected to hold a minimum of a good first degree (upper second class or better) from a UK university or an equivalent qualification if obtained outside the UK.

This project has a Band 1 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).

Informal enquiries may be made directly to the primary supervisor.

References

-Amich J, Dümig M, O'Keeffe G, Binder J, Doyle S, Beilhack A and Krappmann S. Exploration of Sulfur Assimilation of Aspergillus fumigatus Reveals Biosynthesis of Sulfur-Containing Amino Acids as a Virulence Determinant.” Infect Immun. 2016 Mar 24;84(4):917-29

- Bertuzzi M., Schrettl M., Alcazar-Fuoli L., Cairns T., Muñoz A., Walker L., Herbst S., Safari M., Cheverton A., Chen D., Liu H., Saijo S., Fedorova N., Armstrong-James D., Munro C., Read N., Filler S., Espeso E., Nierman W., Haas H., Bignell E. (2014) The pH-Responsive PacC Transcription Factor of Aspergillus fumigatus Governs Epithelial Entry and Tissue Invasion during Pulmonary Aspergillosis The pH-Responsive PacC Transcription Factor of Aspergillus fumigatus Governs Epithelial Entry and Tissue Invasion during Pulmonary Aspergillosis. PLoS Pathog 10(10): e1004413.

- Amich J, Schafferer L, Haas H and Krappmann S. Regulation of Sulphur Assimilation Is Essential for Virulence and Affects Iron Homeostasis of the Human-Pathogenic Mould Aspergillus fumigatus. PLoS Pathog. 2013; 9(8):e1003573.

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