Dr. Simon Johnston, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield
Tuesday 15th November, 1.00 p.m., Stacey Lecture Theatre 1
Serious fungal infection is responsible for over 1 million deaths worldwide each year. In almost all cases these are opportunistic infections that are difficult to treat due to the invasive nature of fungal infection and the limitations of available antifungal agents. A highly conserved component of animal immunity is the ability of innate phagocytic cells to ingest and destroy microbes. However, many microorganisms have evolved the ability to thrive within phagocytes, and use them as a means of driving infection. The interaction of microbes with the host immune system (i.e. host pathogen interactions) is incompletely understood, but available for manipulation with therapeutic gain.
We use a number of experimental and theoretical models to understand host pathogen interactions during cryptococcal infection. In vitro data shows that C. neoformans appears to be able to efficiently parasitise phagocytes, cryptococci survive and proliferates within the phagosome, can escape non-lytically and may use phagocyte as a ‘Trojan horse’. In addition, in vivo data shows that ingestion of cryptococci is restrained very early in infection and that increases in cryptococcal number are driven by intracellular proliferation in phagocytes. Cryptococcus possesses a polymer coat and we have used techniques from theoretical polymer physics to elucidate the physical role of the polymer coat and how it protects cryptococci from ingestion and destruction by phagocytes. I will describe our model of the cryptococcus coat as a polymer brush and present the results of our calculations of the frequency of successful phagocytosis, assuming this is limited by the time taken for the coat to open sufficiently to enable receptor-ligand interactions on the surface of the phagocyte and cryptococcus body respectively. Finally, I will discuss how macrophages might be manipulated to clear cryptococcal infection in the absence of T-cell mediated immunity.