(MRC DTP) Mechanistic basis of the antifungal potency of the airway epithelium

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 based on imaging flow cytometry and microfluidic live-cell imaging, 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 these processes are dysregulated in disease, we now plan to exploit our established single-cell workflows to perform molecular and cellular analyses of the A. fumigatus-AEC interaction in vitro, in 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.

Margherita Bertuzzi UoM profile - https://www.research.manchester.ac.uk/portal/en/researchers/margherita-bertuzzi(a66f2342-f65e-42cf-9144-cf23ceb0d9ff).html
Mike Bromley UoM profile - https://www.research.manchester.ac.uk/portal/mike.bromley.html
Paul Bowyer UoM profile - https://www.research.manchester.ac.uk/portal/paul.bowyer.html
Fungal Research at Manchester - https://www.bmh.manchester.ac.uk/research/domains/infection-immunity-inflammation-repair/infection/fungal/

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships