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Exploring molecular mechanisms of drug resistance and pathogenicity in the filamentous fungus Aspergillus fumigatus


Project Description

A. fumigatus is the primary etiological agent of invasive aspergillosis, a disease that primarily affects individuals who are immunocompromised, and causes 200k life threatening infections annually. A. fumigatus also causes chronic diseases in the ostensibly immunocompetent population which affects around 3 million individuals and leads to c.400k deaths (http://www.gaffi.org/why/fungal-disease-frequency). About 20 million have lifelong conditions caused by an immune hyperactivity to A. fumigatus. Only three classes of drugs are currently recommended for the treatment of aspergillosis with the azole class being recommended for primary therapeutic purposes. Resistance to the azoles is rapidly emerging and for individuals that are infected with a resistant isolate mortality rates are almost 90%. Our understanding of the mechanisms that lead to resistance to the azoles is somewhat limited and novel agents to treat all forms of Aspergillosis are desperately needed.

We have recently discovered 12 transcriptional regulators that are associated with drug resistance in A. fumigatus. The functional role of many of these factors is unknown. In this project our aim is to use our extensive functional genomics toolkit, including tn-seq (a next generation sequencing approach to identify drug sensitive mutants), to fully characterise these transcriptional regulators, identify transcriptional co-regulators and identify routes to disrupting their function. The outputs of this project will support the development of novel diagnostics to detect antifungal resistance and help in the development of new antifungal drugs.

Training/techniques to be provided:
The student will benefit from a diverse and enriching environment and will be trained in the molecular manipulation and characterisation of the human pathogenic fungus Aspergillus fumigatus, molecular techniques including next generation sequencing and qPCR, in vitro assays including MIC determination, mammalian cell culture and in vivo animal models. These skills will provide the student with a competitive advantage for future professional job applications both to academia and industry.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in fungal biology or with an interest in anti-microbial resistance and pathobiology are encouraged to apply.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. 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. Macdonald D, Thomson DD, Johns A, Contreras Valenzuela A, Gilsenan JM, Lord KM, Bowyer P, Denning DW, Read ND, Bromley MJ. 2018. Inducible cell fusion permits use of competitive fitness profiling in the human pathogenic fungus Aspergillus fumigatus. Antimicrob Agents Chemother doi:10.1128/AAC.01615-18.
2. Ahmed WM, Geranios P, White IR, Lawal O, Nijsen TM, Bromley MJ, Goodacre R, Read ND, Fowler SJ. 2018. Development of an adaptable headspace sampling method for metabolic profiling of the fungal volatome. Analyst 143:4155-4162.
3. Gsaller F, Furukawa T, Carr PD, Rash B, Jochl C, Bertuzzi M, Bignell EM, Bromley MJ. 2018. Mechanistic Basis of pH-Dependent 5-Flucytosine Resistance in Aspergillus fumigatus. Antimicrob Agents Chemother 62.
4. Fraczek MG, Chishimba L, Niven RM, Bromley M, Simpson A, Smyth L, Denning DW, Bowyer P. 2018. Corticosteroid treatment is associated with increased filamentous fungal burden in allergic fungal disease. J Allergy Clin Immunol 142:407-414.
5. Misslinger M, Gsaller F, Hortschansky P, Muller C, Bracher F, Bromley MJ, Haas H. 2017. The cytochrome b5 CybE is regulated by iron availability and is crucial for azole resistance in A. fumigatus. Metallomics 9:1655-1665.

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