Research and Professional Experience

The main focus of my research is understanding T cell responses to infection with Plasmodium, the malaria parasite. It has long been known that immunization with irradiated parasites (which do not cause infection) can induce sterile immunity against live parasites injected by infected mosquitoes. A large part of this vaccine-like protection is mediated by CD8+ T cells which can kill parasite infected hepatocytes in the liver. My research addresses a number of critical questions about how protective T cell responses work.

 1.    How do irradiated parasites induce such an effective CD8+ T cell response? Prior to immunization, irradiated parasites have to be dissected out of infected mosquitoes – this probably makes them an unfeasible real-world vaccine. However by learning how parasites can induce protective CD8+ T cells we can learn what features a vaccine should have. We have discovered that irradiated parasites induce the immune system to retain antigen for a period of up to two months. In this time the persisting Plasmodium antigens can continually stimulate and help the expansion of malaria specific CD8+ T cells and thus maximize the immune response.

 2.    What molecules are the targets of malaria-protective immune responses?The malaria parasite has around 5000 genes, which means many molecules could potentially be targets of the immune response. However not all proteins will be presented to CD8+ T cells – a process that is required to initiate an immune response. A critical question is then is “how does the immune system acquire and process antigens from malaria parasites?” Using a novel transgenic system to track antigen presentation we have found that the critical targets of protective immunity (i.e. potential vaccine candidates) are those molecules secreted out of the parasite and into the cytosol of the infected hepatocyte. These proteins can then be processed and presented to CD8+ T cells by the host cell. A critical area for future work will be determining which molecules are secreted and why.

 3.   How do effector CD8+ T cells find and eliminate infected hepatocytes? As an infected mosquito usually injects fewer that 100 parasites, the proportion of infected cells in the liver is tiny. Nonetheless CD8+ T cells are capable of finding these parasites and killing them before they have a chance to initiate a clinical infection. We would like to know how this process works. In collaboration with colleagues at the Instiut Pasteur (Paris, France) we are developing intra-vital imaging techniques to track the behaviour of T cells in the infected liver and understand the events surrounding parasite elimination by CD8+ T cells.

Intra-vital imaging of T cells in the liver: In this project you will use advanced imaging techniques (e.g. multiphoton microscopy) to track the behaviour of CD8+ T cells and Plasmodium (malaria) parasites in the liver. You will investigate the molecules required for T cell homing and migration using knockout and mutant mice. Finally you will determine how disruption of these pathways afftects the ability of T cells to protect against infection.