Post-doctoral Projects

AWARDED IN 2013

[1] Dr Tihana Bicanic ( St George's University of London) and Professor Mihai Netea (Radboud University Nijmegen)

Project title: Deciphering the host genetic factors underlying susceptibility of HIV-infected patients to cryptococcal meningitis

Postdoctoral Fellow: Dr Shichina Kannambath

Proposed start date: June 2014

Lay summary:Cryptococcus neoformans is a fungus inhaled from the environment, yet in most people it never causes any symptoms and remains confined to the lungs. In patients with compromised immune systems, particularly those with HIV infection, the fungus can spread via the bloodstream into the brain, causing meningitis. Despite improvements in antifungal treatment of cryptococcal meningitis over the past 20 years, up to 40% of patients still die, and treatments that supplement the patient’s immune response to the fungus, or vaccines, are needed. To try to understand which immune genes are most important to human defence from Cryptococcus, we will compare extracted DNA from the blood of patients and controls enrolled in clinical trials in Africa, who gave specific permission for this. In this proposal, we first stimulate the immune cells of healthy people with Cryptococcus, to identify immune genes and pathways whose expression it stimulates. Next, we look for differences in these same genes in patients with advanced HIV who got cryptococcal meningitis, versus those who, despite being exposed it, never did (control sample). Finally, within the patients with meningitis, we will look to see which genes were associated with a worse response to treatment, and with death.

[2] Professor Gordon Brown ( University of Aberdeen) and Professor Ken Haynes (University of Exeter)

Project Title: Pattern recognition receptor co-stimulation and Candida glabrata

Postdoctoral Fellow: Dr Ivy Dambuza

Proposed start date: September 2014

Lay summary: Candida glabrata is a fungal organism which can cause disease in immunocompromised individuals, yet little is known about how the host combats these infections. C. glabrata causes long lasting (or chronic) infections in experimental animal models which are characterised by a lack of robust immune responses. We have preliminary evidence that suggests that the chronicity of this infection is due to a defect in the way the immune system “sees” this pathogen. Excitingly, infection could be cured in the animals by artificially stimulating the missing components of the immune system, suggesting a possible route for treatment of this disease in humans. In this application, we wish to verify these preliminary results and characterise the effects of this artificial stimulation on infections with C. glabrata. We also wish to better understand how the immune system “sees” C. glabrata and the reasons for the defective immune recognition of this organism, by determining both the immunological and fungal components that are involved. For this project, we will assemble a crossdisciplinary team of scientists with unrivalled experience and utilize cutting edge molecular, genomic, biochemical and immunological techniques to address these questions.

[3] Professor Neil Gow and Professor Gordon Brown (University of Aberdeen)

Project title: The signature of a pathogen: immune detection of chitin and chitosan

Postdoctoral Fellow: Dr Jeanette Wagener

Start date: August 2013

Lay summary: Chitin is a robust polysaccharide that is found in the cell wall of every fungus, including all those species that cause infections in humans. Chitin is not found in mammals and therefore it has the potential to act as a signature molecule that identifies a fungus as foreign and therefore stimulates the activation of the protective human immune response. However, thus far very little attention has been paid to chitin in terms of immune recognition, and this project aims to fill this important gap in our knowledge. Although chitin is polymerised from only a single sugar by with a single bond, it is structurally diverse, and sometime modified by deacetylation to form the related molecule chitosan. This project will examine how chitin, in all its structural and modified forms activates or represses cells of the immune system. The project rests on over 30 years experience working on chitin synthesis in fungi, and on recent breakthroughs in our laboratories that have begun to identify the receptors of immune cell phagocytes that bind chitin. In addition the project will generate novel diagnostics that can discriminate between chitin and chitosan, which will be useful in detecting various fungal pathogens of man.

[4] Professor Ken Haynes (University of Exeter) and Professor Alistair Brown (University of Aberdeen)

Project Title: Characterisation of novel combinatorial stresses resistant mutants in C.glabrata using forward genetics: exploitation of the newly engineered sexual cycle.

Postdoctoral Fellow: Dr Lauren Ames

Start date: October 2013

Lay Summary: The yeasts Candida albicans and Candida glabrata are the most common fungal pathogens of humans, causing five times as many deaths in the UK as the bacterial pathogen MRSA. Despite this little is known about how these Candida species overcome innate host defences (e.g. patrolling immune cells). We have developed a novel method for analysis of these traits in C. glabrata; mating. Until now C. glabrata was thought to be asexual, but we have engineered strains (using components of the sexually reproductive bakers’ yeast, Saccharomyces cerevisiae) that are able to mate and yield progeny that have inherited genetic information from both parents. We now wish to exploit this technology to determine why C. glabrata is resistant to combinations of two stresses encountered on engulfment by circulating immune cells i.e. increased reactive oxygen species and increased salt concentrations. To achieve this we have made mutants that are even more resistant to this combination of stresses, and by mating these mutants to wild-type parents we will be able to isolate the genes involved. This will allow us to explore the role of the encoded protein in stress resistance, and develop hypotheses about how the organism causes disease. We will also attempt to develop an analogous mating system for C. albicans so that we can use this powerful technique to explore the different way that this species causes infection. In the long-term these experiments should lead to better therapies, immune interventions and diagnosis of life threatening Candida disease.

[5] Dr Julian Naglik (King's College London) and Dr Ernesto Cota (Imperial College London)

Project Title: Structure-function analysis between a Candida albicans hyphal protein and its epithelial surface receptor essential for epithelial activation.

Postdoctoral Fellow: Dr Nessim Kichik

Proposed start date: September 2014

Lay summary: Candida albicans is a major fungal pathogen of humans and gives rise to significant morbidity and mortality in immunocompromised individuals. This project will perform structure-function analysis on a newly discovered interaction event between a key hyphal protein of C. albicans and its surface receptor, which appears to be essential for epithelial activation and induction of immune defences in mucosal tissues. The project will determine the structure of this fungal protein and its active internal region alone and in combination with its epithelial receptor using sophisticated structural analyses based on nuclear magnetic resonance (NMR) and X-ray crystallography. Specific regions within the active internal regions of this fungal protein will be mutated to determine which amino acid residues are essential for receptor interaction, epithelial activation and induction of immune responses. This multidisciplinary proposal will combine protein biochemistry/biophysics, cell signalling and fungal immunology to advance our understanding of fungal-epithelial interactions and has substantial potential for commercial exploitation in industries interested in developing new drugs, vaccines and adjuvants to prevent mucosal diseases and in designing new diagnostic tests and biomarkers for fungal infections.

[6] Professor Gordon Ramage (University of Glasgow) and Dr Carol Munro (University of Aberdeen)

Project Title: Evaluating the clinical outcomes to Candida albicans biofilm formation in candidaemia patients.

Postdoctoral Fellow: Dr Ranjith Rajendran

Start date: 01 October 2013

Lay summary: Candida albicans infections are often biofilm related. These are infections associated with implanted biomaterials and other indwelling medical devices. The ability of this yeast to attach to inert materials, such as catheters allows them to colonise and proliferate without threat from host immunity. These biofilms are thick and tenacious structures that are highly resistant to antifungal therapy. The aim of this project is to investigate why different clinical isolates of Candida albicans are able to form biofilms better than others, and establish whether this is important with respect to the clinical outcome of patients with candidaemia. We intend to gain a thorough understanding of how different clinical isolates maintain their biofilm architecture and investigate whether this plays a role in our ability to manage these infections using antifungal treatment. It is our ultimate aim to be able to treat patients in a targeted approach, so understanding the biological processes that drive biofilm formation will allow us to potentially identify key biomarkers that would enable the targeted delivery of antifungals.