Promoting clearance of infection by targeting interferon gamma signalling and inflammatory activation of macrophages.

Macrophages are both effector cells that directly kill pathogenic microbes and regulator cells that coordinate the response of the immune system to infection. In this project we want to understand how these two aspects of macrophage behaviour interact to decide the outcome of infection:
1) What is the relationship between failure of macrophage activation and increased susceptibility to infection?
2) Can interferon gamma signaling be targeted to promote clearance of infection?
The primary infection we will use in the project is the fungal pathogen Cryptococcus neoformans (http://goo.gl/bJaQco). Cryptococcal infection is both a significant opportunistic infection that causes hundreds of thousands of deaths worldwide each year and an excellent opportunity to understand the relationship between individual macrophage behaviour and infection due to the complicated interactions of Cryptococcus and macrophages (http://goo.gl/IkIf2V).
Macrophages are essential for control of infection yet many microbes are highly resistant to macrophage mediated killing. For example, cryptococci can resist phagocytosis, grow within macrophages if they are taken up and can escape non-lytically by vomocytosis. Critically there are several key macrophage molecular regulators of behaviour (Interferon-gamma, TNF-alpha, Interleukin-10) that we can measure and modulate genetically. In this project we will investigate the mechanistic biology of macrophage activation by interferon gamma and the resulting changes in macrophage behaviour during infection. We will use state of the art imaging in vivo to directly observe immune cell behaviour during infection in our zebrafish models of immunity and infection. Zebrafish have a number of advantages in studying human infections having a highly similar immune system and being able to study both cell and sub-cellular biology in a living organism during infection (http://goo.gl/Vhe8hF). Finally, we aim to use our knowledge of inflammatory activation of macrophages to improve the outcome of infection through therapeutic intervention independent of antibiotics.