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

Qualification: PhD

Department: Respiratory Sciences

Application deadline: 15 March 2021

Start date: September 2021

Overview

Supervisors:

Project description:

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.

Project aims:

  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.

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.

 

 

 
 

Funding

Funding

This 3-year PhD studentship provides:

  • UK/EU tuition fee waiver
  • Annual stipend at UKRI rates (£15,609 for 2021/22)
  • Research Training Support Grant of £5,000 per annum
 

Entry requirements

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.

 

Informal enquiries

Informal enquiries

Project enquiries:

Application enquiries:

How to apply

How to apply

To submit your application, please use the 'Apply' button at the bottom of the page and select September 2021 from the dropdown menu.

With your application, please include:

  • CV
  • Personal statement explaining your interest in the project, your experience and why we should consider you
  • Degree Certificates and Transcripts of study already completed and if possible transcript to date of study currently being undertaken
  • Evidence of English language proficiency if applicable
  • In the reference section please enter the contact details of your two academic referees in the boxes provided or upload letters of reference if already available
  • In the funding section please specify that you wish to be considered for a LeMID 2021 studentship
  • In the research proposal section please provide the name of the project supervisors and project title (a research proposal is not required)
 

Eligibility

Eligibility

UK/EU candidates only