Strategic Research Centre: TrIFIC: Targeting Immunotherapy for Fungal Infections in CF

Understanding which immunotherapies might be effective treatments for complications of Aspergillus fumigatus infection, as alternatives to anti-fungal treatments

Summary

Aspergillus fumigatus is becoming resistant to anti-fungal drugs and immunotherapies are emerging as an alternative treatment. The aim of this SRC is to understand which immunotherapy will most effectively treat Aspergillus complications, and to develop a tailored treatment plan for each person with CF infected.

Background

Approximately 15% of people with CF will contract the fungal infection Aspergillus fumigatus. It can accelerate the decline in lung health in people with cystic fibrosis. Once infected, most people with CF will go on to develop one of two complications of Aspergillus, known as allergic bronchio-pulmonary aspergilliosis (ABPA) or aspergillosis bronchitis (AB) respectively. Treatment is difficult and Aspergillus is becoming resistant to current anti-fungal drugs.

Our bodies fight infection by activating our natural defence system called the immune system. However, sometimes our immune system becomes overactive and makes things worse. Drugs that target the immune system, known as immunotherapies are emerging as an alternative to anti-fungal drugs. They work by reducing this overactivity.

When defending the body against bugs everyone’s immune systems will react in slightly different ways. For people with CF, in addition to these individual differences, their immune system is already at a heightened state of alert. The aim of this SRC is to investigate the effectiveness of immunotherapies as treatments for Aspergillus-related complications in CF, taking into account these individual differences.

Aims of the project

1 Clinical study of Aspergillus infection

The aim of this part of the SRC is to obtain a comprehensive picture of the different ways the immune systems of people with CF respond to Aspergillus infection. The researchers will recruit people with CF to participate in their research, at different stages of infection, and with different complications. They will also recruit people with CF who don’t have Aspergillus infection for comparison.

2 More detailed investigation of aspergillosis bronchitis (AB)

Dr Armstrong-James and colleagues will be looking at three specific types of immunotherapies and investigating if they are likely to be effective against AB. These three immunotherapies work on different parts of the immune system, including: restoring the natural levels of a defence chemical that is low in people with CF, switching off a damaging cell pathway triggered by Aspergillus infection, and ‘turning down’ an exaggerated response to Aspergillus infection that is triggered in people with cystic fibrosis.

3 Effective immunotherapies against allergic bronchio-pulmonary aspergilliosis (ABPA)

In ABPA, tiny particles, known as ‘spores’ of the Aspergillus fungi get into the cells that line the lungs and trigger an allergic response. One part of the allergic reaction is the production of specific proteins called antibodies, and another part is a response of cells within our immune system to the ‘foreign’ particle. The researchers will study the antibody and immune cell reactions of Aspergillus allergy to identify if new immunotherapy treatments developed for other conditions might be effective for people with ABPA.

Who is involved?

Principal investigator: Professor Darius Armstrong-James, Imperial College London

Co-investigators:

• Professor Stuart Elborn, Queens University Belfast
• Professor Adilia Warris, MRC Centre for Medical Mycology, University of Exeter
• Professor Andy Jones, Manchester Adult CF Centre, University Hospitals South Manchester
• Professor Stuart Levitz, University of Massachusetts Medical School, Worcester, USA
• Professor Frank van der Veerdonk, Radboud University Medical School, Nijmegen, The Netherlands
• Professor Rosemary Boyton, Imperial College London