Integrated studies of the targets, regulation and consequences of human immunity to malaria. (360G-Wellcome-092741_Z_10_Z)

This proposal seeks support for an epidemiological and analytical framework developed by us over a number of years in Kilifi, Kenya. Specific elements include longitudinal monitoring of four cohorts of children with detection and careful phenotyping of clinical events in order to relate putative immune functions to immune status. It also includes a carefully documented historical archive of parasite and human samples allowing us to examine the population level consequences of changes in immun ity. Within this framework we will focus on (1) identifying immune targets on the merozoite by using sera of carefully defined immune status to probe both 2D gels and libraries of expressed merozoite proteins; (2) characterizing parasite-derived antigens on the surface of the infected red cell associated with low immunity and virulence; (3) identifying the mechanisms regulating the immune response to malaria; (4) determining which non-antigen genes are subject to immune selection through w hole-transcriptome and whole-genome comparisons of P. falciparum parasites from populations that have been under different intensities of immune selection pressure over a long period of time; and (5) determining the effects of changing transmission on human and parasite populations by a combination of mathematical modelling and next-generation parasite sequencing.