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Antifungal potency of the airway epithelium in health and disease


Faculty of Biology, Medicine and Health

About the Project

Human lungs must balance elimination of a myriad of toxic or pathogenic particles inhaled daily with maintenance of tissue homeostasis to avoid lung disease and ultimately respiratory failure. Aspergillus fumigatus spores are major components of the airborne particulate matter and initiate >3,000,000 chronic and >200,000 invasive diseases annually worldwide. Invasive aspergillosis carries a 50% mortality rate overall; however, mortality rate approaches 100% if diagnosis is delayed or missed, and >75% in certain cohorts of patients. Furthermore, current mortality approaches 100% for infections with azole-resistant isolates, and resistance to azoles (the sole available oral drug against Aspergillus spp.) has risen by 40% since 2006. Thus, there is an urgent need for the development of novel strategies for the clinical management of fungal infection.

Using state-of-the-art single-cell technologies, we have demonstrated that airway epithelial cells (AECs) efficiently kill A. fumigatus spores upon uptake and that this process is altered in chronic obstructive pulmonary disease (COPD), a well-known risk factor for debilitating fungal lung disease. We therefore hypothesise 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. We now aim to determine how healthy AECs recognise and kill A. fumigatus and how this process influences immune responses and is dysregulated in disease, we will exploit an established single-cell workflows and perform molecular, transcriptional and immunological analyses of the A. fumigatus-AEC interaction in vitro, ex vivo and in primary AECs.

Understanding how the lung balances mucosal tissue homeostasis and pathogen clearance upon exposure to inhaled A. fumigatus is of major clinical importance and will inform the identification of immune-modulators to facilitate treatment as well as the limitation of damage caused by this and other respiratory pathogens, leading causes of lung diseases.

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.

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 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

Bertuzzi, Margherita, et al. "The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis." PLoS Pathog 10.10 (2014): e1004413.

Bertuzzi, Margherita, et al. "Anti-Aspergillus activities of the respiratory epithelium in health and disease." Journal of Fungi 4.1 (2018): 8.

Bertuzzi, Margherita, Gemma E. Hayes, and Elaine M. Bignell. "Microbial uptake by the respiratory epithelium: outcomes for host and pathogen." FEMS microbiology reviews 43.2 (2019): 145-161.

Furukawa, T., van Rhijn, N., Fraczek, M. et al. The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus. Nat Commun 11, 427 (2020).

Gago, S., Overton, N.L.D., Ben-Ghazzi, N. et al. Lung colonization by Aspergillus fumigatus is controlled by ZNF77. Nat Commun 9, 3835 (2018).

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