Development and application of fibrotic lung models to study the host microbe interactions in the respiratory tract (pathogens and respiratory flora)

About the Project

Idiopathic pulmonary fibrosis (IPF) is a severe progressive chronic respiratory condition, affecting 3 million individuals globally¹. Life expectancy post diagnosis is roughly 3-4 years, with diagnosis often occurring late^2,3. Exacerbations in IPF are characterised by diffuse alveolar damage in the airways, which also drastically impact life expectancy with studies citing only a 50% survival rate for patients 3 months post exacerbation⁴.

Only recently have researchers began to unveil the role of infection in these acute exacerbation (AE) events. Showing that like in other chronic respiratory conditions, respiratory viruses and bacteria may contribute to IPF disease pathology. Studies indicate that 34.8% of acute exacerbations are due to infection⁵, with AEs largely occurring in winter months again providing evidence for an infectious seasonal viral cause of exacerbations^5-7. In another study exploring AEs in hospitalized patitents, researchers observed respiratory infection with viruses in 17.9% of patients and bacteria in 10.4% of patients⁸. Rhinovirus was the most prevalent virus (7.1%) and Haemophilus influenzae most prevalent bacteria (4.8%). This study further explored the prevalence and impact of co-infection on IPF patients. Co-infection was observed in 59.4% of patients and this was associated with lower FVC and higher mortality rates⁸. Broad-spectrum antibiotics are widely prescribed (56% patients) during acute exacerbations⁹. A randomised control trial to assess the impact of antibiotic use in IPF patients (Co-trimoxazole), found increased quality of life and reduce mortality rates in the test group¹⁰.

The lung microbiome is increasingly recognised as a critical factor in respiratory health and disease. In IPF, the microbial community structure appears altered, with shifts in abundance of key lung commensals and a reduction in overall microbial diversity compared to healthy individuals^11,12. Studies in IPF have shown at the time of diagnosis IPF patients have a higher abundance of bacteria in the airways, but lower bacterial diversity. Veillonella, Neisseria, Streptococcus and Haemophilus species were predominant in IPF airways, and reduced levels of proteobacteria were observed compared to healthy controls^11,13. Skewed microbiome was associated with more rapid disease progression and mortality. In another study the presence of Streptococcus spp and Staphylococcus spp in the lower airways was associated with disease progression and mortality¹⁴. These changes may contribute to a pro-inflammatory airway environment and heightened susceptibility to infections.

Using primary airway epithelial cells (AECs) as a physiologically relevant model, we aim to explore how the presence or absence of key commensal bacteria influences the outcome of viral and bacterial infection in the IPF airway. Understanding these interactions could reveal whether restoring or supporting beneficial microbial communities reduces the severity of infection-driven exacerbations. Such insights may open opportunities for novel therapeutic strategies, including microbiome-targeted interventions, to complement existing antifibrotic and antimicrobial approaches in IPF management.

To do this we will model bacterial and viral infections in the respiratory tract in IPF using primary differentiated airway epithelial cells. Then expand these models to co-culture these organisms with respiratory flora. Using these models, we will evaluate how biofilm formation, inflammation and airway damage as well as other factors differs in health and disease. Focus will be on key respiratory pathogens, Streptococcus pneumoniae, H. influenzae, Staphylococcus aureus, Pseudomonas aeruginosa and Rhinovirus, known to cause exacerbations in individuals with chronic respiratory disease. We will then explore how these readouts differ in the presence of beneficial airway microbes.

The main questions we wish to answer are:

1. Can we develop models to study the impact of infection in IPF?
2. Does biofilm formation, inflammation, and other disease markers differ in health and disease in response to infection in IPF?
3. Can respiratory flora and non-intestinal GRAS (generally regarded as safe) bacteria reduce the impact of infection in the IPF airway?
4. Can primary airway epithelial infection models be used to evaluate novel biotherapeutics and antimicrobial susceptibility.

Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in a related area/subject. An MSc/ MRes degree (merit or above) is desirable. Candidates with experience in bacteriology and/or virology are encouraged to apply. Also experience in working with tissue culture cells/ primary cells is desirable.

Eligibility

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.

Before you Apply

Applicants mustmake direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form – on the application form select PhD Infectious Diseases Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester

If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website View Website