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Understanding the role Aspergillus fumigatus may play in the development of airflow obstruction in severe asthma


Department of Respiratory Sciences

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Dr C Pashley , Prof S Siddiqui , Prof A Hansell No more applications being accepted Funded PhD Project (European/UK Students Only)
Leicester United Kingdom Bacteriology Immunology Microbiology Toxicology

About the Project

Asthma is a common, global condition, affecting >300 million people worldwide and causing considerable morbidity. Asthma is characterized by airflow obstruction and chronic airway inflammation but is heterogeneous in its presentation. Fungal infection may play an important role in severe asthma. Historically fungi were considered a rare complication of asthma, exemplified by Allergic Bronchopulmonary Aspergillosis (ABPA), an accepted endotype of asthma [1]; however, a significant proportion of individuals with Aspergillus fumigatus sensitisation do not meet criteria for ABPA but are at high risk for the development of airflow obstruction [2]. Using a high volume culture approach [3] we have shown that A. fumigatus can be cultured frequently in patients with moderate to severe asthma, but it is not clear how infection causes airflow obstruction nor which patients should receive anti-fungal treatment.

We hypothesise that chronic bronchial colonisation with A. fumigatus causes airflow obstruction.

The Aims of this project are:

  1. To determine the clinical characteristics of people with severe asthma who have recurrent sputum A. fumigatus culture positivity
  2. To investigate the in vitro effects of A. fumigatus on human airway smooth muscle cells

Research Plan

Serial sputum samples will be obtained from severe asthma patients at stable state attending the “difficult asthma” clinic. Sputum samples will be divided and used for routine microbiology, high volume fungal culture and DNA extraction. The DNA will be analysed for A. fumigatus quantitative PCR and mycobiome analysis and compared with clinical data including lung function data, levels of antibodies against A. fumigatus in the blood and evidence of lung damage on CT scan images.

Primary human airways smooth muscle cells will be used to investigate the in vitro effects on human airways caused by the presence of A. fumigatus on cell-induced contraction of extracellular matrix, and on calcium signalling.

Expected outcomes and impact

The research will provide important new insights into the contribution of fungi to severe asthma. Understanding the clinical characteristics of patients with severe asthma who are colonised with A. fumigatus is key to understanding how to design clinical trials.

The in vitro study will help us understand how A. fumigatus can cause airflow limitation, and will open up avenues for possible interventions to prevent the damage occurring.

Experimental Methods, environment and supervision

You will learn a broad range of skills involved in undertaking clinically relevant science. You will be provided with training in a wide range of molecular and mycological techniques, including, DNA analysis, bioinformatics, culture, in vitro assays and Real Time PCR.

You will be based in the Department of Respiratory Sciences at the main campus of the University of Leicester, interacting closely with the clinical team at Glenfield hospital to recruit patients, obtain sputum, and record clinical outcomes and with the NIHR Leicester Biomedical Research Centre (BRC).  You will benefit from three supervisors with distinct but complementary skill sets. Dr Pashley is a lecturer in aerobiology and clinical mycology, with > 15 years’ experience investigating the role of fungi in asthma and other respiratory conditions. Prof Siddiqui is a clinical professor of Airways Disease. He leads national programs in stratified medicine in severe asthma and stratified medicine trials of biologics in ABPA. Prof Hansell is a Professor of Environmental Epidemiology and the director of Leicester’s NIHR Health Protection Research Unit (HPRU) in Environmental Exposures and Health, which is currently exploring the impact of indoor exposure to fungi and volatile organic compounds in asthma.

Entry requirements:

Applicants are required to hold/or expect to obtain a UK Bachelor Degree 2:1 or better, or overseas equivalent in a relevant subject. 

The University of Leicester English language requirements apply where applicable.

Application advice:

To apply please refer to: https://le.ac.uk/study/research-degrees/funded-opportunities/lemid-pashley-2021

Project enquiries: Dr. Catherine Pashley ([Email Address Removed])

Application enquiries to [Email Address Removed]


Funding Notes

This 3-year PhD studentship provides:
• UK/EU tuition fee waiver
• Annual stipend at UKRI rates (£15,609 indicative rate for 2021/22)
• Research Training Support Grant of £5,000 per annum

References

1. Lotvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127(2):355-360.
2. Woolnough KF, Richardson M, Newby C, et al. The relationship between biomarkers of fungal allergy and lung damage in asthma. Clin Exp Allergy. 2017;47(1):48-56.
3. Pashley CH, Fairs A, Morley JP, et al. Routine processing procedures for isolating filamentous fungi from respiratory sputum samples may underestimate fungal prevalence. Med Mycol. 2012;50(4):433 – 438.
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