2015 Projects

2015 Awards:

[1] Dr Alex Brand (University of Aberdeen)

Collaborator(s): Dr Jeremy Craven (University of Sheffiled)

Project title: The role of Paxillin in the organization of directional growth by Candida albicans hyphae

PhD Student: Angela Lopez

Start date: 01 October 2015

Lay summary:

Most humans are harmlessly colonised by the fungus, Candida albicans, which lives primarily in the gut. However, this fungus can become a life-threatening problem if it disperses into the bloodstream of immunocompromised patients and spreads into internal organs. To invade its host, the fungus forms long, penetrating cells called hyphae. These hyphae steer as they grow, enabling them to probe host surfaces, find penetration sites and invade the tissue below. This research aims to expand our understanding how hyphae steer so we can find ways to disrupt the process and reduce invasion. We have identified a potential signalling pathway which affects hyphal steering rather like having faulty wheels on a supermarket trolley. Normal hyphae can change direction when they need to, but our mutants are either locked in one trajectory and cannot change direction, or they cannot grow straight for long and bend when they are not supposed to. Our aim is to find out how this pathway functions and whether it controls other aspects of cell growth, especially the ability to penetrate tissue. Because this is a key process in disease progression, it constitutes a strong target for antifungal drug development.

[2] Dr Kerstin Voelz (University of Birmingham)

Co-investigator(s): Professor Robin May ( University of Birmingham), Professor Gordon Brown and Dr Carol Munro (University of Aberdeen)

Project title: Elucidation and modulation of innate immune responses during zygomycete infections.

PhD Student: Herbert Itabangi

Start date: 01 October 2015

Lay summary:

Although zygomycosis has historically been considered a rare disease, advances in medical care and an increasingly aging population have resulted in a recent rise in the incidence of this fungal infection. Enhanced management of susceptible individuals with predisposing conditions (e.g. diabetes, iron-overload, immune-suppressive therapy, cancer and trauma injury) has improved patient prognosis for other disorders, but now provides enhanced opportunities for opportunistic zygomycosis to establish.

Currently available antifungal therapy is ineffective against zygomycete infection and treatment thus involves extensive removal of infected tissue, usually leading to long-term disability. To date, little research has been undertaken on zygomycetes and the immune responses to zygomycete infections is not well understood. This project will decipher the initial immune response to infections with fungal spores. The research will decipher how our immune system recognises spores and what signals are engaged to activate and control the immune system after infection with zygomycete fungi. Ultimately, we hope that our approach will highlight novel immunomodulatory strategies to harness the host immune system to improve patient outcomes.

[3] Professor Ken Haynes (University of Exeter)

Project title: Targeting synthetic lethal and re-sensitizing interaction partners of PDR1 gain of function muatations as a paradigm for treating drug resistant Candida glabrata infections.

PhD Student: Daniel Sayon Djofang

Start date: 01 October 2015

Lay summary:

Candida species are the fourth most commonly isolated pathogens from nosocomial blood stream infections and are responsible for at least 400,000 life threatening infections annually and in the UK cause five times as many deaths per annum than the much more widely known MRSA. Infection is very difficult to diagnose and even with best practice management, mortality rates approach 50%. The incidence of Candida glabrata infection has grown rapidly over the last 20 years, and it is now responsible for ~25% of candidosis case. The reason for this increasing incidence of C. glabrata infection is not fully understood, but it is clear that this species has a higher innate tolerance to commonly administered azole antifungals, the principle therapeutic option for Candida infections, and can rapidly acquire drug resistance coincident with therapy. The principle mediators of this tolerance and acquired resistance are gain of function mutations in the PDR1 gene, which encodes a regulator of other genes. Targeting antifungal development to Pdr1 related processes, thus seems logical. We will identify genes that interact antagonistically with PDR1 gain of function mutations and then attempt to copy this interaction with small molecules (drugs). These experiments will not only yield valuable new biological information they will also translate into applied outcomes, in particular the discovery of proteins that can be targeted therapeutically in the context of drug resistant Candida infection.

[4] Dr Duncan Wilson ( University of Aberdeen)

Co-investigator(s): Professor Neil Gow (University of Aberdeen)

Collaborator(s): Professor Lars Erwig and Dr Donna MacCallum (University of Aberdeen)

Project title: A giant impact: elucidating the role of Candida albicans Goliath cells on host-pathogen interactions.

PhD Student: Dhara Malavia

Start date: 01 October 2015

Lay summary:

Candida albicans, one of the most common fungal pathogens of humans, is responsible for millions of cases of superficial infections (e.g. thrush) and hundreds of thousands of invasive infections each year. These invasive infections are deadly: even if treated with front line antifungal therapy, patients have less than a 60% chance of survival, underscoring the desperate need for novel therapeutic strategies. One of the key features of C. albicans is its ability to grow in different morphological forms, including ovoid yeast cells and chlamydospores, as well as filamentous forms (hyphae and pseudohyphae). This morphological plasticity is believed to play a crucial role during infection. We have found that manipulating the nutritional status of C. albicans results in the formation of exceptionally large cells, and that this is associated with alterations in the expression of genes involved in remodelling the fungal cell surface. In the current project, we aim to elucidate the physiological properties of these “Goliath cells”. Specifically, we predict that this novel morphology may be differentially recognised by the human immune system and therefore play a key role during infection.

[5] Professor Alistair Brown ( University of Aberdeen)

Co-investigator(s): Professor Gordon Brown and Dr Donna MacCallum (University of Aberdeen)

Project title: The transition from fungal commensalism to systemic infection

PhD Student:  Dr Prashant Sood

Start date: 01 October 2015

Lay summary:

Candida albicans is a major opportunistic pathogen that affects millions worldwide. The transition from commensalism to pathogenicity is central to the establishment of Candida infections. The transition from gastrointestinal (GI) colonisation to systemic infection is particularly relevant because pharmacological or surgical perturbation of protective gut barriers significantly enhances the likelihood of systemic candidiasis. This transition is associated with host-fungus interactions that depend not only upon host immune status, but also the adaptive responses of the fungus. Yet there is a fundamental gap in our understanding about how C. albicans adapts to gut microenvironments and how this adaptation affects the transition to pathogenicity. We will test our prediction that adaptation to local environmental stresses and nutrients in the GI tract protects the fungus against

phagocytic killing, thereby promoting the evasion of immune defences and the establishment of systemic infections. The project will test this prediction by defining the regulatory networks that drive GI adaptation and colonisation, and that are required for the transition to systemic disease using an established model of GI colonisation. The student will receive a multidisciplinary training involving genomic screens, network construction, fungal molecular dissection, immunological characterisation,novel in vivo imaging technologies, and infection models.