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:
- To determine the clinical characteristics of people with severe asthma who have recurrent sputum A. fumigatus culture positivity
- 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]
Continue with Facebook
