We will establish a core to support three Pilot Projects that add mechanistic insight to the correlates of protection that will be established in Project 1 and Project 2. In the major projects, existing clinical studies in diverse immunization and challenge models will be used to identify patterns of leukocyte function, antigenspecific response, cytokine secretion and gene expression that are associated with either protection from infection, or amelioration of pathology, in living human subjects. In parallel, three mechanistic Pilot Projects will explore the biology ofthe interaction between malaria parasites and host cells in vitro. In Pilot Project 1, we will determine the effect of Plasmodium falciparum sporozoites on human Kupffer cells, which are widely believed to be a crucial portal of entry used by the parasites to gain access to hepatocytes. In Pilot Project 2, we will analyze the interaction between human anti-malaria cytotoxic effector cells raised against genetically modified vaccine strains, and infected hepatocytes. To achieve this we will use an optimized method to obtain hepatocyte-like cells direct from stem cells, and thus derive cell cultures highly susceptible to infection with P. falciparum sporozoites. In Pilot Project 3 we will directly identify the CD8+ T cells that are engaging malaria-infected hepatocytes, selectively harvest that small minority of cells by laser-mediated ablation of other cells, and perform RNA profiling on these antigen-specific CD8+ cytotoxic T cells. This will generate a transcriptome analysis of those CTL that are specially activated by malaria vaccines. All three of these Pilot Projects will provide mechanistic insight into the interaction between human malaria parasites and the immune system, with emphasis on pre-erythrocytic stages.
Taking the results of these Pilot Projects together with the two main Projects, we will develop a better understanding of the process of human malaria infection, the way malaria parasites avoid immune defenses,and how vaccines work. This will help in the design of next-generation experimental vaccines, leading towards the long-term goal of malaria eradication.
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