Additional funds for the study Implications of bacterial evolution and health: the Neisseria model. (360G-Wellcome-047072_Z_96_D)

Many pathogens of man are antigenically variable, using changes in the structure of cell components that are exposed to the immune system as a means of evading immune attack. This strategy poses substantial difficulties for the development of public health interventions, particularly vaccination. In addition, the evolution of antigenic variants and the accommodation of such variants within the structural constraints of the cell surface are important fundamental phenomena. The existence of pathogenic species as 'strains' that are antigenically distinct has been known for most of this century but the evolution of 'pathogenic' strains and the reasons for their stability in the face of recombination and diversifying selection remain poorly understood. This project will improve our understanding of the evolution of antigenic variants by the acquisition and analysis of data from populations of the human pathogen Neisseria meningitidis specifically to apply, test, and develop models of the evolution of antigenic variation. The range and rate of antigenic variation in each sub-population of meningococci will be established and the following specific hypotheses will be addressed: (i) that meningococci have a range of population structures that are associated with specific epidemiologies; (ii) that the antigenic diversity of distinct meningococcal sub-populations differ in both level of diversity and in the mutational mechanisms most important in generating that diversity; (iii) that meningococcal populations are structured into strains by human immune interactions, and that any differences observed in (i) and (ii) are the result of differing selection pressures in diverse epidemiological contexts; (iv) that nucleotide sequence data can be used to predict antigens that are likely to be of use in vaccine design. These data will be used to validate and develop further models of antigenic variation and its effect on clonal divergence and epidemiology.