Research

Infectious diseases account for 25% of all deaths, are the biggest cause of death in the young and the leading cause of death in low-income countries (WHO Infectious disease report). New and improved therapies for infectious diseases are needed throughout the world.

We want to understand why the certain infectious cannot be controlled by the immune system, especially where there is a specific immune defect, such as in AIDS. Our research is focussed on the fungal pathogens Cryptococcus neoformans and C. gattii but we also have projects looking at Candida, Staphylococcus and Streptococcus pathogenesis. 

See below for a technical and lay introduction to our research on Cryptococcus or click here for more information on some our current projects. We are also very interested in developing technology and methods for visualising the living immune system and for automated image analysis.

To hear Simon talk about our bird macrophage work on the BBC World Service click here.

 

Technical Introduction

Cryptococcus neoformans and C. gattii are fungal pathogens of humans and the causative agents of cryptococcosis, associated with significant mortality causing death through meningitis. C. neoformans is a major pathogen of the immunocompromised, especially AIDS patients, and causes hundreds of thousands of deaths per year.  The vast majority of these deaths occur in Africa where mortality ranges from 30% to over 50%. However, even with optimal clinical management in the developed world mortality is still 5-11%. Additional at risk immunosuppressed groups include those on immunosuppressive therapy (e.g. organ transplantation and those with rheumatoid arthritis) or those with certain haematological malignancies (e.g. chronic lymphocytic leukemia). In contrast, C. gattii is predominantly a pathogen of immunocompetent individuals and is localised to the tropics and sub-tropics. However, there are increasing numbers of cases outside of this region, in particular the Vancouver Island and Pacific Northwest outbreaks, and these highlight how particular strains of C. gattii are hypervirulent in comparison to other isolates of C. gattii. C. neoformans has also been implicated in infection of large numbers of HIV-uninfected individuals in certain regions (e.g. China, Korea and Vietnam). This is often in the absence of any discernible immunocompromise, and as with the North America outbreak these cases may be due to novel hypervirulent strains.

Macrophages, are an essential part of the immune response to infection, for the front-line destruction of pathogens and for regulation of both the innate and adaptive arms of the immune system. Macrophages are likely the first immune cells to encounter cryptococci and by evading or manipulating phagocytes, particularly macrophages, Cryptococcus is able to cross many, if not all of the immune barriers that prevent the progression of infection, in both the immunocompromised and immunocompetent disease states. Both in vitro and in vivo data show that Cryptococcus is capable of efficiently parasitising macrophages. Cryptococcus survives within the mature phagosome as well as manipulating phagosome maturation, can escape non-lytically (via vomocytosis), proliferates within the phagosome and may use macrophages as a ‘Trojan horse’.

Lay Introduction

When the immune system does no function properly, for example, in cancer, age related disease and during infection with HIV (the virus that causes AIDS), we are vulnerable to microbes that normally do not cause disease. One such microbe is the fungus Cryptococcus. Fungi that cause disease in humans are uncommon and those that cause serious disease are very rare. However, serious fungal infections are much more common in those with weakened immune systems, with an estimated 1 million cases and hundreds of thousands of deaths due to Cryptococcus infection worldwide each year. I want to understand why we become vulnerable to infections such as Cryptococcus and how this understanding can lead to new treatments and therapies.

What we already know is that Cryptococcus is able to avoid some parts of the immune response. For example, Cryptococcus is able to escape immune cells called macrophages whose job it is to eat and digest microbes. Cryptococcus is able to do this by being ejected from the macrophage in a process called vomocytosis. Vomocytosis is one of many examples of something a microbe does in a dish but we do not know what the consequences are in a real infection.

 

 

 

 

 

Join the Lab

We always welcome enquiries if you are interested in joining the lab. To find out more, click here.