Clinical PhD Fellowships

AWARDED IN 2014

[1] Dr Adilia Warris ( University of Aberdeen) and Professor Gordon Brown (University of Aberdeen)

Project Title: A. nidulans and Chronic Granulomatous Disease: exploring a unique interaction

Clinical PhD Fellow: Dr Gill King

Start date: September 2014

Lay Summary:

Patients with chronic granulomatous diseases (CGD) have an extremely high-risk to develop invasive fungal infections and often these infections are fatal. The reason for this is that they have an insufficient immune system, their white blood cells (the so-called soldiers of the body) are not able to kill fungal organisms properly. The defect in their white blood cells will also cause the spontaneous release of inflammatory mediators leading to organ damage. Invasive fungal infections in patients with a compromised immune system are mainly caused by Aspergillus fumigatus, although patients with CGD exclusively suffer from invasive aspergillosis caused by A. nidulans, being the 2nd most common observed cause of invasive aspergillosis in this patient population. Importantly, those two Aspergillus species are causing different disease patterns and infections caused by A. nidulans are more often fatal. Our recent studies showed that the interaction between the two Aspergillus species with the immune system clearly differ. The present project will explore these differences in more detail. By doing so, we hope to find new ways of treatment to improve patient management and to increase life expectancy.

[2] Dr Tihana Bicanic (St George's University of London) and Professor William Hope (University of Liverpool)

Project Title: The relationship of antifungal resistance and pharmacokinetics with therapeutic response to a fluconazole/flucytosine induction regimen for HIV-associated Cryptococcal meningitis

Clinical PhD Felllow: Dr Neil Stone

Start date: October 2014

Lay Summary:

Cryptococcal meningitis is a form of fungal meningitis which commonly affects people with advanced HIV/AIDS, causing over half a million deaths each year. It is always fatal if left untreated. The best current known treatment is a 2-week course of an antifungal drug(Amphotericin B) with a second antifungal(flucytosine), followed by a long course of another antifungal (fluconazole) to prevent recurrence. Amphotericin B and flucytosine are often unavailable in many African settings where the burden of Cryptococcal disease is highest, and patients are treated with fluconazole from the start. This drug is much slower at killing the fungus in the brain, and resistance can develop and cause relapse. We will study two groups of patients being treated for Cryptococcal meningitis. One in Zambia, receiving fluconazole and flucytosine in combination, and another in Tanzania, receiving fluconazole alone. This project aims to assess whether resistance is a significant problem, establish to what extent laboratory-determined resistance of Cryptococcus to fluconazole, combined with the levels of the antifungals in patients’ blood and cerebrospinal fluid, determine whether a given patient responds to treatment, and explain the exact genetic mechanism of Cryptococcal resistance to fluconazole.

[3] Dr Darius Armstrong-James (Imperial College London) and Dr Adilia Warris (University of Aberdeen)

Project Title: Defining the role of the calcineurin-NFAT signalling in innate fungal immunity to Aspergillus fumigatus in lung transplant recipients

Clinical PhD Fellow: Dr Amelia Bercusson

Start date: January 2015

Lay Summary:

Advances in cystic fibrosis (CF) care have improved outcomes with many individuals now living into adulthood. Life expectancy is still reduced, primarily due to lung disease. Improved management of bacterial infection has led to an emerging problem with fungal organisms, which are almost impossible to eradicate. Fungal infection is also a common and life-threatening complication of lung transplantation, which is a major treatment option for patients with CF. These patients are at greater risk of developing fungal infections than non-CF transplant recipients, with 50% of our local CF transplant population having aspergillosis. Our studies have shown that transplant drugs impair the calcineurin-NFAT immune response of macrophages to A. fumigatus. Our hypothesis is that the defective chloride channels found in CF further impair macrophages calcineurin-NFAT responses, making them extremely susceptible to Aspergillus infection. Our aim is to better understand these defective macrophages responses to Aspergillus in transplant recipients and specifically in CF patients. We will also study whether new CFTR modulators for CF restore defective macrophage responses to Aspergillus fumigatus, in addition to their effects on epithelial cells. If this is shown, then CF patients could benefit from continuing CFTR modulators post-transplant, thereby improving clinical outcome and quality of life.