Investigating the epigenetic regulation of pneumococcal virulence

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In late winter the bacterium Streptococcus pneumoniae asymptomatically colonises the nasopharynx of up to seventy percent of children; it is also responsible for approximately 2.000.000 deaths worldwide due to complications of community acquired pneumonia. For over 80 years it has been recognized that when isolated from blood the bacterium forms opaque dome shaped colonies on solid laboratory medium whereas it forms flat transparent colonies when isolated from the nose. In general genetic regulatory events form the basis of the complex behaviour of any cell, both bacterial and eukaryotic; however no genetic differences could be identified between pneumococcal cells in the two distinct phase variable forms. Epigenetic regulatory mechanisms have in recent years been discovered to have a significant impact on bacterial cells. For the first time we have clear preliminary data that show that a phase variable epigenetic regulatory mechanism influences the capacity to colonise and cause invasive disease in this important human pathogen. The proposed project is aimed to elucidate the function of the phase variable restriction modification system responsible for this epigenetic regulation. The two main objectives instrumental to this aim are (i) to perform a molecular characterization of the mechanism by which the restriction modification system influences cell physiology and (ii) to describe the molecular mechanism by which the system recombines creating the epigenetically distinct subpopulations. Understanding and modelling the molecular nature of these processes is aimed to shed light on the intrinsic mechanisms by which a bacterium that is able to colonize asymptomatically in most children can rapidly change "behaviour" becoming one of the main human pathogens causing acute invasive disease. Such understanding is expected to be instrumental for designing improved intervention strategies both for prevention and treatment.