Funded in 2007

Development of a vaccine against fungal infections
Dr Brahm Segal
Departments of Medicine and Immunology Roswell Park Cancer Institute, Buffalo, New York. £97, 248 over two years.

Infection caused by the fungi Aspergillus is a serious cause of illness and mortality in individuals with Chronic Granulomatous Disorder (CGD) and in many other diseases affecting the immune system.  Funds from CGD RT were used to support two interrelated projects: the development of an Aspergillus vaccine and mechanisms by which the enzyme affected in CGD, NADPH oxidase, regulates inflammation.  The strategic development of the vaccine was found to be crucially dependent on understanding more about how the defect in CGD influences immune cell interactions and causes inflammation.  The project generated a heat shock protein (HSP) -expressing Aspergillus as a vaccine candidate; elucidated mechanisms by which NADPH oxidase regulates cell responses and identified potential therapeutic targets in CGD (e.g., Nrf2 activation, immunomodulation of T-cell responses).  Overall, this project gave a greater insight into how to better design immune –based therapies, including vaccination.

In 2009 on the basis of the results generated through CGDRT funding Dr Segal was awarded a five-year, $2.2 million dollar research grant for a proposal, entitled, 'Role of NADPH oxidase in regulating inflammation’ by the National Institutes of Health in the USA. 

This award will help further elucidate mechanisms by which NADPH oxidase regulates inflammation that may pave the way to novel therapeutics.  Click here to see more

 Non-oxidative Polymorphonuclear Leukocyte Mediated Anti-Aspergillus Activity Professor Judith Rhodes and Dr Jarrod Fortwendel University of Cincinnati, Ohio, USA $63187 over one year

The aim of the project was to determine the mechanisms by which killing of aspergillus fungus can be achieved so fungal infections can be better treated in CGD. The project helped better define the role of the PKA pathway that is central to the infectious and damaging properties of Aspergillus in CGD. It was found when a certain part of the pathway was altered the virulence of Aspergillus was reduced in such a way to cause little spread of the fungus to other tissues. Further work showed the decrease in virulence resulting from altering this pathway was due to a mechanism other than increased susceptibility to oxidative damage. This project has achieved a greater understanding and knowledge of an important regulatory pathway for Aspergillus growth and virulence in CGD. This will help in the development of better anti-fungal drugs for people with CGD and for many other conditions.

Development of a Model to Understand Chronic
Aspergillosis in CGD Professor Tom Rogers, Dr Elaine Bignell, Dr Ken Haynes & Professor Arst Herb.
Imperial College Faculty of Medicine, London £72,000 over three years, Ph. D Studentship, started in 2004

The work found out more about how the healthy immune system clears Aspergillus lung infections and how and why the response of CGD patients differs from this and causes severe problems. The research work was aimed at more closely replicating the development of human aspergillosis in animal models of CGD and studying the cellular differences between infection in CGD and healthy mice. Both types of mice were infected with the fungus Aspergillus and the study compared what cell types were infected with the fungus Aspergillus were present in the lungs using special immune system markers over different periods of time. This allowed a picture to be built up of how the disease progresses. Identifying where in the lung tissue particular types of cells were found helped piece together how the immune response was coordinated in the CGD model in response to Aspergillus infection. This project has already identified some key differences in gene marker expression in response to Aspergillus fungi between healthy and the immuno-compromised state where disease develops.