Genotypic and phenotypic markers of resistance in Aspergillus fumigatus and their impact on outcomes in chronic pulmonary aspergillosis
About the Project
Chronic pulmonary aspergillosis (CPA) is a progressive infection affecting patients with chronic lung disease. It significantly affects quality of life and mortality. Only around 60% respond to treatment with antifungals, while around 20% will relapse after treatment. Development of resistance is the major cause of treatment failure, although the risk factors and its evolution during treatment are not understood. This project will explore the dynamics of resistance to azole antifungals in the fungus Aspergillus fumigatus by assessing both patient and microbial factors.
Stage 1: Determination of risk factors for development of resistance in CPA
Clinical and demographic information of patients with CPA seen at the National Aspergillosis Centre will be extracted. The emergence of azole resistance during treatment will be documented and correlated with all patient factors including antifungal treatment.
Stage 2. Identification of mutation rate in Aspergillus strains as a predictive factor of subsequent resistance development and outcomes
A. fumigatus isolates from the above patients will be subjected to mutation rate analysis and tolerance screening. Mutation rates and tolerance characteristics will be correlated with subsequent resistance development, after correction for demographic and clinical factors identified during stage 1.
Stage 3. Genetic risk factors of azole resistance in chronic Aspergillus infection
Aspergillus strains will be subjected to whole genome sequencing. Serial isolates from individual patients will be analysed so that their phylogenetic linkage can be established. In addition, the mutation rate and tolerance phenotypes determined in stage 2 will be linked to specific resistance mechanisms identified with genetic analysis.
This project will lead to the identification of patient-related factors for resistance development in CPA. This will in turn identify the patients at highest risk for failure of treatment, informing treatment decisions.
Entry Requirements
Candidates are expected to hold (or be about to obtain) a minimum upper second-class honours degree (or equivalent) in Biology or a related area / subject. Candidates with experience in molecular biology approaches or with an interest in mycology or microbiology are encouraged to apply.
How to Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Medical Mycology.
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 www.internationalphd.manchester.ac.uk
Equality, Diversity & Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
Funding Notes
Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website View Website
References
Scott J, Valero C, Mato-López Á, Donaldson IJ, Roldán A, Chown H, Van Rhijn N, Lobo-Vega R, Gago S, Furukawa T, Morogovsky A, Ben Ami R, Bowyer P, Osherov N, Fontaine T, Goldman GH, Mellado E, Bromley M, Amich J. Aspergillus fumigatus Can Display Persistence to the Fungicidal Drug Voriconazole. Microbiol Spectr. 2023 Mar 13;11(2):e0477022. doi: 10.1128/spectrum.04770-22. Epub ahead of print. PMID: 36912663; PMCID: PMC10100717.
van Rhijn N, Hemmings S, Storer ISR, Valero C, Bin Shuraym H, Goldman GH, Gsaller F, Amich J, Bromley MJ. Antagonism of the Azoles to Olorofim and Cross-Resistance Are Governed by Linked Transcriptional Networks in Aspergillus fumigatus. mBio. 2022 Dec 20;13(6):e0221522. doi: 10.1128/mbio.02215-22. Epub 2022 Oct 26. PMID: 36286521; PMCID: PMC9765627.
Kosmidis C, Otu A, Moore CB, Richardson MD, Rautemaa-Richardson R. Isavuconazole Therapeutic Drug Monitoring during Long-Term Treatment for Chronic Pulmonary Aspergillosis. Antimicrob Agents Chemother. 2020 Dec 16;65(1):e01511-20. doi: 10.1128/AAC.01511-20. PMID: 33077653; PMCID: PMC7927812.
Van Rhijn N, Bromley M, Richardson M, Bowyer P. CYP51 Paralogue Structure Is Associated with Intrinsic Azole Resistance in Fungi. mBio. 2021 Oct 26;12(5):e0194521. doi: 10.1128/mBio.01945-21. Epub 2021 Oct 5. PMID: 34607450; PMCID: PMC8546618.
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