About the Project
Inhalation of Aspergillus fumigatus spores cause >3,000,000 chronic and >200,000 invasive diseases annually worldwide. Invasive aspergillosis carries a 50% mortality rate overall, but mortality rate approaches 100% if diagnosis is delayed or missed and it is >75% in certain cohorts of patients, such as COPD sufferers. Additionally, current mortality approaches 100% for infections with azole-resistant isolates, which have increased by 40% since 2006. Thus, there is an urgent need for the development of novel strategies for the clinical management of fungal infection.
Previous work from the supervisory team has demonstrated that airway epithelial cells (AECs) efficiently kill A. fumigatus spores upon uptake and that this process is altered in patients with chronic obstructive pulmonary disease (COPD) and upon viral co-infection, both well-known risk factors for debilitating fungal lung disease. Therefore, the overarching hypothesis of their work is that AECs critically contribute to healthy clearance of inhaled A. fumigatus spores and that dysregulation of protective AEC responses represents a potent driver of aspergillus-related diseases.
Using optimised protocols for high-throughput in vitro infection modelling with primary human AECs, we now wish to decipher the mechanistic basis of dysfunctional clearance of A. fumigatus spores in at-risk patients. To this end, we propose to perform first-in-field molecular, transcriptional and immunological analyses of the A. fumigatus-AEC interaction in vitro in primary AECs from healthy donors, COPD patients stratified according to disease severity and with viral co-infection.
With the overall aim of obtaining a mechanistic understanding of the antifungal potency of the airway epithelium and its dysfunction in disease, this research ultimately aims to inform the identification of immune-modulators to facilitate clinical management of these and other lethal respiratory infections and ultimately reduce their disease burden in humans.
Training
Benefiting from a rich and diverse research environment, the student will be trained in the molecular manipulation and characterisation of the human pathogenic fungus Aspergillus fumigatus; single-cell technologies such as Imaging flow-cytometry and Live-cell microfluidics imaging; RNA-seq and CyTOF; extraction, manipulation and in vitro infection of primary human epithelial cells with A. fumigatus; 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 fungal infection biology 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 Infection, Immunity and Respiratory Medicine.
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.
Equality, Diversity and 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
References
Dancer P, Pickard A, Potocka W, Earle K, Fortune-Grant R, Kadler K, Bertuzzi M, Gago S. Mutual inhibition of airway epithelial responses supports viral and fungal co-pathogenesis during coinfection. bioRxiv 2022.04.13.488236;
doi: https://doi.org/10.1101/2022.04.13.488236
Bertuzzi M, Howell GJ, Thomson DD, Fortune-Grant R, Möslinger A, Dancer P, VanRhijn N, Motsi M, Du X, Codling A, Sash R, Demirbag M, Bignell EM. Epithelial uptake of Aspergillus fumigatus drives efficient fungal clearance in vivo and is aberrant in Chronic Obstructive Pulmonary Disease (COPD). bioRxiv 2022.02.01.478664;
doi: https://doi.org/10.1101/2022.02.01.478664
Gago S, Overton NLD, Bowyer P. CRISPR-Cas9-Mediated Gene Silencing in Cultured Human Epithelia. Methods Mol Biol. 2021;2260:37-47. doi: 10.1007/978-1-0716-1182-1_4. PMID: 33405030.
Ben Ghazzi N, Moreno-Velásquez S, Seidel C, Thomson D, Denning DW, Read N, Bowyer P & Gago S. Characterisation of Aspergillus fumigatus Endocytic Trafficking within Airway Epithelial Cells Using High-Resolution Automated Quantitative Confocal Microscopy. Journal of Fungi. 2021.
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