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Translating genome and proteome information into immune recognition

Final Report Summary - GENOMES_TO_VACCINES (Translating genome and proteome information into immune recognition)

Genome information is accumulating rapidly and it encompasses a wide range of species, including humans and many pathogens, among others. It is now possible to completely sequence microbial genomes within a period ranging from days to months, and genomics can therefore be used as a powerful starting point to investigate the biology of any pathogen of interest. The translated protein sequence information constitutes a significant input to the immune system.

Indeed, the immune system considers peptides as one of its key targets, and it has devoted an entire arm - that of T cells, which essentially control specific immune responsiveness - to peptide recognition. T cells are specific for peptides presented in the context of Major histocompatibility complexes (MHC). Prior to their presentation, these peptides were generated in the cytosol by limited proteolytic fragmentation of all available protein antigens, then translocated to the Endoplasmic reticulum (ER) and specifically sampled by the MHC for subsequent presentation. The MHC is extremely polymorphic and the peptide binding specificity varies for the different polymorphic MHC molecules. The net effect of this complicated system is that each individual presents to their T cells a unique and highly diverse peptide imprint of the on-going protein metabolism.

The scientific rationale of GENOMES_TO_VACCINES was one of understanding, describing and predicting how the immune system handles proteins; or more specifically, of how it generates, selects and recognises peptides. Generating these predictive tools amounts to translating genomes/ proteomes into immunogens, and it enabled a new and rational approach for vaccination and immunotherapy.

GENOMES_TO_VACCINES has generated efficient biochemical assays for three different major steps in the generation of T cell epitopes. This includes the proteolytic fragmentation of protein antigens (proteasome), the peptide translocation event (TAP), and the peptide selection and presentation event (MHC). New biochemical assays were used to generate data representing the above events. Significant progress in generating a new and improved method for the generation of high-density peptide arrays was also made, and the researchers hope to implement this technology in the generation of orders of magnitude for more biochemical data in the future.

The data obtained so far has been used to generate bioinformatics tools capable of predicting the outcome of these events in silico and to initiate the iterative process leading to improved predictions. For validation purposes, the researchers have generated a set of data using peptides extracted from cellular MHC, as representative examples of how the immune system works under natural conditions. They integrated the prediction tools and demonstrated that such an integrated predictor is more successful in predicting natural epitopes. GENOMES_TO_VACCINES has made these tools generally available as web-based services, and will eventually also host the data itself.

Finally, the utility of these tools was demonstrated through the prediction of human T cell responses. Initially, the researchers showed the speed of these tools by performing a complete epitope scanning of the SARS virus. Subsequently, they performed a complete epitope scanning of Influenza A isolates, and tested the predicted peptides both in biochemical MHC binding assays, but, more importantly, in healthy influenza convalescents.

The latter study identified 13 new influenza epitopes, which covered virtually the entire population. These epitopes were selected for being highly conserved, and notably, they all encompassed the current bird flu isolates. The ability to translate genomic information into immune recognition will form the basis for a rational approach to immunotherapy (including vaccination), which the researchers believe will serve the policy objectives of enhancing the quality of life for European Union citizens.